Autoimmunity Reviews 12 (2012) 174–194

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Autoimmunity Reviews
journal homepage: www.elsevier.com/locate/autrev

Review

Lupus nephritis: A critical review

Andrea T. Borchers a, Naama Leibushor a, Stanley M. Naguwa a, Gurtej S. Cheema a,
Yehuda Shoenfeld b, M. Eric Gershwin a,⁎
a
Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA 95616, United States
b
Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center (affiliated to Tel-Aviv University), Tel-Hashomer 52621, Israel

a r t i c l e i n f o a b s t r a c t

Article history: Lupus nephritis remains one of the most severe manifestations of systemic lupus erythematosus associated
Accepted 12 August 2012 with considerable morbidity and mortality. A better understanding of the pathogenesis of lupus nephritis is
Available online 8 September 2012 an important step in identifying more targeted and less toxic therapeutic approaches. Substantial research
has helped define the pathogenetic mechanisms of renal manifestations and, in particular, the complex role
Keywords:
of type I interferons is increasingly recognized; new insights have been gained into the contribution of
Tolerance
Immune complexes
immune complexes containing endogenous RNA and DNA in triggering the production of type I interferons
Interferons by dendritic cells via activation of endosomal toll-like receptors. At the same time, there have been
Autoantibodies considerable advances in the treatment of lupus nephritis. Corticosteroids have long been the cornerstone
of therapy, and the addition of cyclophosphamide has contributed to renal function preservation in patients
with severe proliferative glomerulonephritis, though at the cost of serious adverse events. More recently, in
an effort to minimize drug toxicity and achieve equal effectiveness, other immunosuppressive agents,
including mycophenolate mofetil, have been introduced. Herein, we provide a detailed review of the trials
that established the equivalency of these agents in the induction and/or maintenance therapy of lupus
nephritis, culminating in the recent publication of new treatment guidelines by the American College of
Rheumatology. Although newer biologics have been approved and continue to be a focus of research,
they have, for the most part, been relatively disappointing compared to the effectiveness of biologics in
other autoimmune diseases. Early diagnosis and treatment are essential for renal preservation.
© 2012 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
2. Histological classification of lupus nephritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175
3. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
3.1. Breaking of tolerance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 176
3.2. Pathogenesis of LN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177
3.3. Amplification mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
3.3.1. The type I interferon axis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178
3.3.2. T cells in lupus nephritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
3.3.3. IL-17 producing T cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
3.4. Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
4. Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
4.1. Treatment of class I and II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
4.2. Treatment of class III and IV . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
4.2.1. The NIH and Euro-Lupus (ELNT) regimens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
4.2.2. Mycophenolate mofetil (MMF) as induction therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
4.2.3. AZA plus methylprednisolone for induction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
4.2.4. MMF or AZA for maintenance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184

⁎ Corresponding author at: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, 451 Health Sciences Drive, Suite
6510, Davis, CA 95616, United States. Tel.: +1 530 752 2884; fax: +1 530 752 4669.
E-mail address: megershwin@ucdavis.edu (M.E. Gershwin).

1568-9972/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.autrev.2012.08.018
 A.T. Borchers et al. / Autoimmunity Reviews 12 (2012) 174–194 175

4.3. Treatment of membranous LN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184

4.4. Biological agents as further treatment options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
4.4.1. Belimumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
4.4.2. Rituximab and ocrelizumab . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
4.4.3. Abatacept and other biologicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
5. Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
6. Outcome/prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
6.1. Remission and flares . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
6.2. Progression to ESRD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
6.3. Renal replacement therapy treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 186
6.4. Patient survival . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
6.5. Future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187
Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188

1. Introduction
Systemic lupus erythematosus (SLE) is an autoimmune disease
that can affect essentially any organ or tissue. It is the prototypic
autoimmune disease [1,2]. One of its most severe manifestations is
lupus nephritis (LN), which remains a cause of substantial morbidity
and mortality, either secondary to kidney disease, or as a result of
intense immunosuppressive drug toxicity [3–10]. The incidence and
prevalence of SLE overall generally range from 1 to 5/10 5 and 20 to
150/10 5, respectively, with women being affected 9 times more
frequently than men [11]. The frequency of SLE is 2- to 8-fold higher
in non-European populations, particularly those of African ancestry.
LN epidemiology data are limited. One study from northwest
England yielded incidence and prevalence of 0.4/10 5 and 4.4/10 5,
respectively [12]. The onset of SLE in most populations occurs most
commonly during the third and fourth decade of life and somewhat
later in populations of European descent. Approximately 15–20% of
patients experience the onset of SLE prior to 18 years of age. The
frequency of renal involvement is particularly high in juvenile-onset
SLE, ranging from 50% to 80% in most cohorts described to date
[13–18] and does not differ with ethnicity [14]. In contrast, LN is
less frequent in patients with late-onset SLE (≥50 years), with
fewer than 30% of patients affected [19]. Renal disease may be the
first manifestation of SLE, but most commonly occurs within a year
of diagnosis, and almost always within 5 years, but can occur any
time throughout the course of the disease [20,21]. Age-standardized
prevalence differs significantly by ethnicity, being 3.5/10 5 for white,
13.3 for Indo-Asian, 64.6 for Afro-Caribbean and 66.7 for Chinese
patients. This is in agreement with numerous cohort studies demon-
strating that SLE patients of European descent have the lowest fre-
quency of renal disease (20–45%) [20,22–24], whereas 50–70% of
SLE patients develop nephritis in African American and certain
Asian, Arab, Hispanic, indigenous and mestizo populations [11].
Non-European patients, in particular those with African ancestry,
often develop LN earlier in the course of the disease [21,25–29].
African ancestry has been identified as an independent predictor
of developing renal disease at any time during the disease course,
particularly in close proximity to SLE diagnosis in various multiethnic
cohorts [21,26–28]. Texan Hispanic ethnicity independently predict-
ed the development of LN in close proximity to SLE diagnosis, but
not renal involvement in general [27,28]. A variety of other demo-
graphic, serological, clinical and genetic factors have also been
implicated [21,26–28,30], and education [28] and socioeco-
nomic variables were identified as risk factors for developing
LN [21,26,31–35]; the “ethnicity” variable itself was found to be
explained in part by admixture, particularly of African American an-
cestral genes, and in part by a composite measure of socioeconomic
status, but at least 45% of this variable remained unexplained [36].
Overall, ethnicity and socioeconomic status combined accounted for
only about 22% of the variability in the occurrence of renal involve-
ment. In several cohort studies, male SLE patients were shown to
have more renal involvement and worse outcome compared to their
female counterparts [37–40]. However, this gender disparity was
not shown in other cohorts [41,42]. We should also note that much
of our knowledge or mechanism is based on murine models [43–51].
2. Histological classification of lupus nephritis
Glomerulonephritis (GN) is the most common form of renal
disease in patients with SLE, but is frequently accompanied by
tubulointerstitial and/or vascular lesions (such as thrombosis second-
ary to antiphospholipid syndrome). A variety of other nephropathies,
including renal amyloidosis, focal segmental glomerulosclerosis,
minimal-change disease, IgA and IgM nephropathy, necrotizing
glomerulitis, sarcoidal and NSAID-induced tubulointerstitial nephri-
tis, and thin basement membrane disease have also been described
in patients with SLE [52]. Lupus nephritis can present as nephritic
and/or nephrotic syndrome with various combinations of edema,
constitutional symptoms, proteinuria, hematuria, impaired renal
function, abnormal lipid profile and hypertension. The clinical pre-
sentation does not correlate very well with the type and severity of
renal biopsy histology findings. Hence, kidney biopsies remain the
gold standard for establishing the diagnosis of LN, for determining
the activity and chronicity of the disease and formulating the appro-
priate type of treatment.
The histological changes found in biopsy samples of LN kidneys
are highly diverse, ranging from mild mesangial involvement,
through proliferative forms of GN to end stage fibrosis, including
endothelial injury, endocapillary proliferation and membranous LN
characterized by podocyte injury and nonproliferative capillary wall
lesion. Importantly, various combinations of these lesions can co-
exist. Consequently, there have been several attempts to classify LN
biopsies according to the most prominent pattern of histologic
abnormality, first by the WHO and more recently by the International
Society of Nephrology and the Renal Pathology Society (ISN/RPS)
[53,54] (see Table 1). Both classification systems are exclusively
concerned with the glomerular pathology; tubulointerstitial and
vascular lesions are not addressed, although the ISN/RPS classification
contains a strong recommendation to report such lesions. The
most important changes in the ISN/RPS compared to the WHO
classification include: 1) class I no longer includes a “Nil” category,
i.e., the complete lack of renal abnormalities by light microscopy,
immunofluorescence, and electron microscopy is excluded from the
ISN/RPS classification system; 2) qualitative and quantitative differ-
ences are introduced into the distinction between class III and class
IV lesions; 3) class IV is subdivided into a global and a segmental sub-
group; 4) rather than subdividing class V into subgroups depending
on the presence or absence of class II, III, or IV lesions, the use of
176 A.T. Borchers et al. / Autoimmunity Reviews 12 (2012) 174–194
Table 1
WHO and ISN/RPS classifications of lupus nephritis (LN).
WHO
Class Normal glomeruli
I a. Nil (by all techniques)
b. Normal by light microscopy, but deposits by IF or electron microscopy
Class Pure mesangial alterations
II a. Mesangial widening and/or mild hypercellularity (+)
b. Moderate hypercellularity (++)
Class Focal segmental glomerulonephritis
III
a. With active necrotizing lesions
b. With active and sclerosing lesions
c. With sclerosing lesions
Class Diffuse glomerulonephritis (severe mesangial, endocapillary or
IV mesangiocapillary proliferation and/or extensive subendothelial deposits)
a. Without segmental lesions
b. With active necrotizing lesions
c. With active and sclerosing lesions
d. With sclerosing lesions
Class Diffuse membranous glomerulonephritis
V a. Pure membranous glomerulonephritis
b. Associated with lesions of class II
c. Associated with lesions of class III
d. Associated with lesions of class IV
Class Advanced sclerosing glomerulonephritis
VI
GN = glomerulonephritis; IF = immunofluorescence; LM = light microscopy.
WHO = World Health Organization.
ISN/RPS = International Society of Nephrology and the Renal Pathology Society.
combined designations is encouraged in the ISN/RPS classification
system (e.g., class III and class V or class IV and class V).
The most controversial of these changes in the ISN/RPS classification
system is the subdivision of class IV into diffuse global and diffuse seg-
mental LN. This was based largely on the results of a single investigation
by Najafi et al. [55] demonstrating that patients with focal segmental
GN with ≥50% of glomeruli involvement (WHO class III ≥50%) had sig-
nificantly worse 5- and 10-year renal survival rates compared to pa-
tients with WHO class IV, Vc or Vd lesions, and were less likely to
enter remission compared to class IV. Several studies examined wheth-
er the subclassification of class IV LN into segmental (involving less than
half of the glomeruli) versus global (involving more than half of the glo-
meruli) truly reflects clinical differences or adds prognostic value
[56–63]. Class IV-global (class IV-G) was associated with more signifi-
cant proteinuria and nephrotic syndrome, higher serum creatinine,
hypertension, and more pronounced hypocomplementemia, although
these differences were not always consistent, and did not always
reach statistical significance. Generally, other typical histologic findings
of class IV-G lesions were endocapillary proliferation and wire loops,
whereas fibrinoid necrosis was more frequent in class IV-S defused
segmental lesions [57,58,62,63]. A variety of other morphological
features have also been found to differ significantly between classes
IV-S and IV-G in individual studies, but the overall results are highly
inconsistent. This is partly due to high interobserver variability for clas-
sifying renal biopsy specimens, regardless of whether the WHO 1995 or
the ISN/RPS system was used. In one study where interobserver agree-
ment was scored, only 15% of 54 individual histological characteristics
were scored as “good”, whereas 54% of these items reached “poor” [63].
Interestingly, when the ISN/RPS classification system was applied to
the biopsies of the patients studied by Najafi et al. [55], only half of those
ISN/RPS
Minimal mesangial LN
Normal glomeruli by LM, but mesangial immune deposits by IF
Mesangial proliferative LN
Pure mesangial hypercellularity of any degree or mesangial matrix expansion by light
microscopy, with mesangial immune deposits
Maybe a few isolated subepithelial or subendothelial deposits visible by IF or electron
microscopy, but not by LM
Focal LN
Active or inactive focal, segmental or global GN involving b50% of all glomeruli
Class III (A) active lesions: focal proliferative LN
Class III (A/C) active and chronic lesions: focal proliferative and sclerosing LN
Class III (C) chronic inactive lesions with glomerular scars: focal sclerosing LN
Diffuse LN
Active or inactive diffuse, segmental or global GN involving ≥50% of all glomeruli; divided into:
– diffuse segmental (IV-S) LN when ≥50% of the involved glomeruli have segmental
lesions (involving less than half of the glomerular tuft);
– diffuse global (IV-G) LN when ≥50% of the involved glomeruli have global lesions.
Class IV-S (A) active lesions: diffuse segmental proliferative LN
Class IV-G (A) active lesions: diffuse global proliferative LN
Class IV-S (A/C) active and chronic lesions: diffuse segmental proliferative and sclerosing
LN
Class IV-G (A/C) active and chronic lesions: diffuse global proliferative and sclerosing LN
Class IV-S (C) chronic inactive lesions with scars: diffuse segmental sclerosing LN
Class IV-G (C) chronic inactive lesions with scars: diffuse global sclerosing LN
Membranous LN
Global or segmental subepithelial immune deposits or their morphologic sequelae by LM
and by IF or electron microscopy, with or without mesangial alterations
Class V LN may occur in combination with class III or IV, in which case both will be diagnosed
Class V LN demonstrates advanced sclerosis
Advanced sclerotic LN
≥90% of glomeruli globally sclerosed without residual activity
previously classified as WHO class III ≥50% were switched to ISN/RPS
class IV-S, the remainder were classified as IV-G [64]. This clearly
demonstrates that WHO III ≥50% and class IV differ from ISN/RPS
classes IV-S and IV-G, respectively. The authors suggest that important
clinical and prognostic information is lost by adopting the ISN/RPS
class IV-G and IV-S categories. This may explain why none of the analy-
ses reported to date has been able to demonstrate a significant differ-
ence in prognosis or in outcome between patients with ISN/RPS class
IV-G and IV-S lesions at an initial biopsy [57,58,60–63]. However, global
lesions in a second biopsy obtained after therapy may have prognostic
value since all of the patients with global lesions experienced doubling
of serum creatinine, but only 36% of those with segmental lesions
experienced doubling of serum creatinine. However, this difference
did not reach statistical significance due to the small number of subjects
(n=17) [57]. Most of these studies using the ISN/RPS classification
system did not subdivide class IV lesions into active (A), active and
chronic (A/C) and chronic (C). Activity/chronicity score seems to be of
high prognostic value as Japanese patients with LN class IV-G (A)
responded well to therapy, and none experienced doubling of serum
creatinine, compared to those with LN class IV (A/C), whose renal
outcome was significantly worse [60].
3. Pathogenesis
3.1. Breaking of tolerance
SLE is characterized by the production of numerous autoanti-
bodies, which predominantly target nuclear antigens, and these are
strongly implicated in the pathogenesis of LN [65]. Although the rea-
son for the targeting of nuclear antigens is still not fully understood,
 A.T. Borchers et al. / Autoimmunity Reviews 12 (2012) 174–194
some evidence suggest that it relates to the expression of lupus
autoantigens on the surface of apoptotic blebs [66], increased apopto-
sis, and the defective clearance of apoptotic bodies [67,68]. There are
indications that apoptotic nucleosomes, i.e., chromatin, are the initial
immunogen in SLE, with subsequent spreading of the reactivity to
histones and dsDNA [69]. However, there are patients with anti-
dsDNA antibodies who do not display detectable levels of anti-
chromatin reactivity, hence, there are probably other mechanisms
leading to anti-dsDNA reactivity.
Usually apoptotic bodies are cleared rapidly from the circulation
and undergo secondary necrosis if clearance is deficient. It has been
shown that a subset of nucleosomes released from cells in the late
stages of apoptosis, i.e., secondary necrosis, contains high mobility
group box protein 1 (HMGB1). This is a protein found only in SLE
patients' sera that can both stabilize nucleosome structure and
turn into a proinflammatory molecule once it is released from cells
[70]. HMGB1 nucleosome complexes are capable of inducing
dendritic cell (DC) maturation and of stimulating the release of pro-
inflammatory cytokines from macrophages in a TLR-2-dependent
manner [70]. Immunization of mice with late apoptotic nucleosomes
induces the production of antibodies to dsDNA, to histones and – in
some mice – to extractable nuclear antigens, again in a TLR-2-
dependent manner. This suggests that HMGB1-nucleosome com-
plexes may be a crucial factor in breaking tolerance to nuclear anti-
gens. Patients with SLE exhibit both elevated serum HMGB1 as well
as antibodies to HMGB1 [71–73]. An association of serum HMGB1
levels with renal disease, particularly active renal disease, has been
suggested [71,73], but a longitudinal study did not reveal significant
reduction in serum HMGB1 concentrations during therapy [72].
HMGB1 was also found to be strongly expressed in renal biopsy tissue
from all WHO classes of LN, with intense immunostaining outlining
the glomerular endothelium and to a lesser extent in the mesangium,
whereas control tissue demonstrated almost exclusively nuclear
staining [72]. The precise role of renal target tissue expression of
HMGB1 remains to be determined.
3.2. Pathogenesis of LN
While the pathogenesis of LN remains incompletely understood,
major insights are derived from a variety of animal models which cap-
ture multiple features of SLE, and in particular glomerulonephritis.
These models include MRL/lpr, NZB/W F1 hybrid (NZB/W) mice, and
the NZB/W-derived congenic strains like NZM 2328 and NZM 2410.
There is evidence from these animal models that glomerulonephritis
is initiated by renal deposition or formation of immune complexes
(ICs), resulting in the activation of complement and Fcγ receptors
(FcγR). The complement system has a dual role in SLE and LN. Homozy-
gous deficiency of C1 components and, to a lesser extent, C2 and C4 is
the strongest single genetic risk factor for the development of SLE,
most likely because of the complement's role in clearing apoptotic
bodies and ICs [74]. Recently anti-C1q Abs specific to the globular
head region of the molecule have been described [75]. Some of these
autoantibodies are able to inhibit the interactions of C1q with IgG and
CRP, suggesting their contribution to functional C1q deficiency as well
as to defective clearance of apoptotic materials and ICs as observed in
many patients with SLE and LN. On the other hand, the results of animal
studies clearly implicate complement activation, particularly of the
alternative pathway, in glomerular injury [76,77]. Although there is
also clear evidence for an important role of FcγR engagement in the
development of glomerulonephritis [78–80], the exact contribution of
the specific activating and inhibiting receptors to tissue injury has not
yet been fully elucidated. Another crucial step in the activation of
immune pathways that amplify the pathogenic mechanisms in LN is
the costimulation of FcγRs and endosomal toll-like receptors (TLRs)
[81,82] (as will be discussed in more detail below).
177
Renal immune deposits are found in virtually all patients with SLE,
yet a substantial proportion of them retain normal histology by light
microscopy [83,84]. Other patients have histological abnormalities,
frequently representing proliferative or membranous glomerulone-
phritis, but never developing clinical manifestations of renal disease
[84–86]. Such cases of “silent nephritis” indicate that the progression
from immune deposits to morphological alterations, and to the devel-
opment of clinical symptoms requires other events or factors. Those
must play a role in either enhancing susceptibility to, or protecting
from these processes. This is further supported by studies in certain
murine models where experimental animals fail to develop inflam-
matory renal disease despite marked deposition of ICs [78,87] or
where clinical disease does not develop despite considerable glomer-
ular pathology [88].
Although more than 150 different antigens can be targeted in SLE, nu-
clear antigens are most strongly implicated in the pathogenesis of LN.
These include antibodies against DNA (both double stranded and single
stranded), chromatin, histone, SSA, SSB, and ribonucleoprotein. All of
these as well as anti-C1q antibodies have been eluted from postmortem
kidney tissues of patients with LN, and were found in higher serum quan-
tities compared to surrogate (the initial supernatant of glomeruli)
[89–94]. Of note, enrichment of anti-histone and anti-chromatin reactiv-
ity was markedly more frequent compared to enrichment of anti-double
stranded DNA antibodies [89]. This supports the hypothesis that chroma-
tin constitutes the initial target of autoreactivity in SLE.
Anti-dsDNA antibodies are a hallmark of SLE and represent the most
thoroughly investigated antibody specificity. They are detectable long
before the development of SLE and LN [95] and are found more
frequently and at higher titers in patients with LN compared to SLE
patients without renal involvement [96,97]. However, this is not an
entirely consistent finding, and the ability of anti-dsDNA antibodies to
predict renal flares remains controversial [98]. Anti-dsDNA antibodies
demonstrate evidence of somatic hypermutation, indicating that their
development is antigen driven. The most direct evidence for the patho-
genicity of anti-dsDNA antibodies comes from the demonstration of its
production and subsequent renal deposition and proteinuria in severe
combined immunodeficiency (SCID) mice following intraperitoneal
hybridoma administration [99]. Despite great efforts it has not been
possible to fully define the characteristics which make certain anti-
dsDNA antibodies pathogenic versus inertic. Isotype certainly plays a
role, and IgG subclass also appears to be more pathogenic than IgA or
IgM, most likely because of differential affinities for complement and
FcγR. The antibody specificity has been implicated in determining the
localization of IC deposits as well as the subsequent pathological and
clinical changes [100]. In addition, nephritogenic anti-dsDNA antibodies
often display high avidity as well as cross-reactivity with a variety of
intracellular and extracellular antigens. Their charge may also be impor-
tant [96,101–104].
How anti-dsDNA and other autoantibodies deposit in the kidney is
also not fully elucidated. The original theory that ICs in the circulation
become passively trapped in glomeruli is not supported by evidence,
and is now considered unlikely. It has been hypothesized that cross-
reactivity with certain extracellular matrix molecules of the glomerular
basement membrane, such as laminin, type IV collagen, and heparan
sulfate, determines the glomerular localization of anti-dsDNA antibodies
[105]. Other cross-reactive targets include intracellular structural pro-
teins, such as α-actinin-4 and myosin [102,104–106]. Importantly,
there are data suggesting that mesangial cells of MRL/lpr mice express
significantly higher levels of surface α-actinin compared to those of
Balb/c mice [102]. This suggests that antigen availability may be a
major determinant of whether LN develops or not. Interestingly, immu-
nization of non-autoimmune BALB/c mice with α-actinin resulted in
high titers of antinuclear antibodies (ANA) that cross-reacted with chro-
matin, histones, and Sm/RNP, but not with dsDNA, anti-single stranded
DNA, or cardiolipin [107]. Mice immunized with α-actinin developed
higher levels of renal immuloglobulin (Ig) deposition and proteinuria
178 A.T. Borchers et al. / Autoimmunity Reviews 12 (2012) 174–194
compared to adjuvant-immunized control mice. However, several stud-
ies indicate that, in vivo, there is no direct binding of anti-dsDNA anti-
bodies to glomerular basement membrane components in both
experimental animal models and in SLE patients [108–110]. Instead,
these studies provide evidence that the binding of these autoantibodies
to membrane structures is mediated by interactions between antibody-
bound nucleosomes and heparan sulfate. These nucleosomes may derive
from the circulation, or may arise locally from increasing apoptosis of
intraglomerular cells, secondary to established nephritis.
While it is generally assumed that breaking of tolerance to nuclear
antigens is central to LN pathogenesis, there is clear evidence from
animal models that renal IC deposition, severe proteinuria and chron-
ic glomerulonephritis can develop in the absence of ANA, anti-DNA
and anti-nucleosome antibodies [111,112]. This implies that auto-
antibodies without nuclear specificity can be nephritogenic. A non-
nuclear antigen of special interest in LN is C1q. In different studies,
antibodies to C1q, which recognize epitopes on the collagen-like
region of this complement component, are found at highly variable
portions in SLE patients (ranging from 17 to 70%, depending
partly on the assay system and the cut-off used for positivity)
[97,113–116]. Serum C1q antibody positivity strongly correlates
with renal disease, with higher prevalence and titers in patients
with LN compared to those without, and in patients with active
renal disease compared to those with inactive renal disease
[97,113,114,116–119]. Rising titers were found to predict renal flares
better than did anti-dsDNA antibodies, particularly in patients with
proliferative GN [120,121], whereas anti-C1q reactivity decreased or
even disappeared during successful therapy [117,119,121]. Several
groups of investigators found that lack of anti-C1q antibodies had
up to 100% negative predictive value [117,118,122,123], suggesting
that active LN, particularly class III or IV, does not occur in the absence
of this reactivity. Lack of assay standardization and the failure to
obtain serum samples at the time of the biopsy may explain
the lower negative predictive values found in other studies
[114,116,124]. There are data from a non-autoimmune experimental
model suggesting that anti-C1q autoantibodies do not capture circu-
lating C1q, but instead bind to the C1q present in ICs deposited in
glomeruli, resulting in local complement and FcγR activation [125].
This could explain why most patients demonstrate glomerular Ig
and C1q deposits, but overt renal disease develops only in those
who also express anti-C1q antibodies. Direct binding of anti-C1q anti-
bodies to nucleosomes and glomerular endothelial cells with subse-
quent enhancement of C3 deposition, particularly in the presence of
anti-DNA antibodies, may also result in increased complement activa-
tion and glomerular injury [126]. However, patients with LN without
anti-C1q antibodies at the time of biopsy have been described, includ-
ing up to one-third of patients with class III and IV lesions [127], and
renal flares can also develop in the absence of detectable anti-C1q
antibodies [121].
The sum of the seven identified antibody specificities found to be
enriched in kidney eluates of patients with LN accounts for less than
10% of the total eluted IgG in most patients (the range being b 1% to
a maximum of 41%) [89]. This suggests that a variety of other autoan-
tibody specificities are deposited in lupus kidneys, and may partici-
pate in renal pathology.
3.3. Amplification mechanisms
3.3.1. The type I interferon axis
Type 1 interferons (IFNs) are crucial mediators of anti-viral immune
responses and are important regulators of the proliferation, differentia-
tion, survival and function of almost every immune cell type. Yet, they
also play an important role in autoimmune diseases, including SLE.
IFNα in particular can induce the differentiation of monocytes into
DCs and can activate immature myeloid DCs (mDCs). This in turn acti-
vates autoreactive T cells and provides help to autoreactive B cells,
thereby increasing the production of autoantibodies. In addition, acti-
vated mDCs can stimulate CD8+ T cells to differentiate into cytotoxic
effector T cells. By causing tissue damage, such cytotoxic T lymphocytes
(CTL) generate autoantigens, in particular nucleosomes, that can then
be presented by mDCs to ultimately activate yet more autoreactive
B cells. Several lines of evidence strongly implicate type I IFNs in the
pathogenesis of SLE: 1) treatment of patients with viral diseases or
malignancies with exogenous IFNα can induce autoantibodies and
lupus-like disease; 2) approximately half of SLE patients harbor elevat-
ed serum levels of INFα [128,129] or demonstrate a so-called “type I IFN
gene signature”, i.e., increased expression of type I IFN-regulated genes
in peripheral blood [130,131]. This upregulation is being attributable
almost exclusively to IFNα [132]; 3) serum from some SLE patients is
capable of inducing the differentiation of blood monocytes into DCs in
an IFNα-dependent manner [133]; 4) several studies, though not all,
demonstrate an association between a type I IFN gene signature and
disease activity [134–136], although in longitudinal studies, changes
in disease activity do not necessarily correlate to the expression level
of IFN-inducible genes [137,138].
Data on an association of type I IFN gene significance with LN,
particularly active renal disease, are somewhat more controversial
[130,134–136], with the largest study to date not detecting any asso-
ciation [139]. Note that this study used a reporter assay to measure
serum IFNα activity. In contrast, the type I IFN signature or IFNα
score may actually reflect not only increased IFNα activity but also
raise individual sensitivity to this cytokine [140]. Importantly, it has
recently been reported that resident renal cells can be a major source
of IFNα in a murine model of immune-mediated nephritis and are,
therefore, likely to contribute to end-organ disease [141].
In various murine models of SLE or SLE phenotypes, deficiency of
type I IFN receptor (IFN-RI) markedly attenuates autoantibody pro-
duction and reduces the frequency of renal disease [142–144]. This
is with the notable exception of MRL/lpr mice, in which IFN-RI defi-
ciency induces autoantibody synthesis and worsens renal pathology,
suggesting a role for type I IFN in suppressing B cell activation in
this particular model [145]. Conversely, administration of adenovirus
expressing IFNα results in prolonged production of this cytokine, en-
hances autoantibody production and accelerates the onset of protein-
uria and glomerulonephritis in the NZB/W and related mice models of
lupus [146–148]. It also renders these mice as more resistant to treat-
ment that usually prevents the onset of proteinuria in conventional
NZB/W mice and is associated with a higher relapse rate after
remission-inducing therapy of established kidney disease [149].
The major producers of IFNα are plasmacytoid DCs (pDCs). Evidence
has been accumulating that endogenous RNA or DNA in the form of ICs
can induce IFNα production in the pDCs of healthy volunteers
[82,150–152]. RNA-containing ICs signal through Toll like receptor
(TLR)7, whereas DNA containing ICs signal through TLR9 [151,153].
Both TLRs are endosomal receptors, and FcγRIIa was shown to be the
cell membrane receptor that delivers DNA-containing ICs to the intra-
cellular lysosomes containing TLR9 [82]. There are data strongly
suggesting that IC-induced secretion of IFNα by pDCs depends on the
presence of HMGB1 in these complexes, and requires the HMGB1 re-
ceptor, RAGE [153]. Interestingly, C1q can inhibit IC-induced production
of IFNα by pDCs. However, it remains unclear whether this is due to a
direct effect of C1q on pDCs [154], or occurs via an indirect mechanism
involving preferential binding of C1q-ICs to macrophages [155]. In
either case, these studies reveal another role for C1q in SLE pathophys-
iology and emphasizes that the functional C1q deficiency frequently ob-
served in SLE patients may contribute to the continuous production of
IFNα.
ICs containing chromatin or nucleosomes are also able to activate
murine mDCs, resulting in a distinct cytokine pattern consisting of in-
creased TNFα production in the absence of IL-12 induction [81]. Such
ICs also induce production of B cell activating factor (BAFF), which
plays an important role in B cell proliferation and activation. Whereas
 A.T. Borchers et al. / Autoimmunity Reviews 12 (2012) 174–194
cytokine induction was found to depend mostly on a pathway involv-
ing FcγRIII and TLR9, the induction of BAFF was TLR9-independent
and could therefore be an important mechanism in humans, whose
mDCs do not express TLR9 [156].
Another mechanism for activation of pDC by endogenous DNA in-
volves neutrophil extracellular traps (NETs). These are web-like struc-
tures that arise from a specific type of cell death called NETosis and
consist mainly of chromatin and neutrophil proteins. Interestingly,
anti-RNP antibodies induce NETosis in neutrophils of about two-thirds
of SLE patients, but not in those of healthy individuals, and this process
requires FcγRII and TLR7 [157]. Upon in vitro stimulation with the pro-
tein kinase C activator, phorbolmyristase acetate (PMA), neutrophils
from SLE patients released more NET-DNA compared to those from
healthy controls [158]. A subset of SLE patients was also found to exhibit
defective degradation of NETs, and this defect was significantly associ-
ated with the presence of renal disease [159]. Importantly, NETs are
capable of triggering pDC activation and IFNα production in a TLR9-
dependent manner [157,158]. NET uptake by PDCs requires the pres-
ence of the antimicrobial peptide LL37. This was further enhanced by
the presence of human neutrophil peptides (HNPs) [158]. Anti-LL37
and anti-HNP antibodies were detected in 41 and 58% of SLE patients,
respectively. These antibodies were found to enhance the FCγRII-
mediated internalization of DNA-containing ICs. NETs also contain
HMGB1, another protein that has been shown to be essential for
IC-induced IFNα production by pDCs [153].
Stimulation through TLR7 and TLR9 was found to protect human
pDCs and other TLR9 positive cell types (conventional DCs and B cells)
from glucocorticoid-induced cell death. Inhibition of TLR7 and TLR9 in
vitro and in vivo restored glucocorticoid sensitivity, and reduced the ex-
pression of IFN-regulated genes [160]. This suggests that exaggerated
TLR7 or TLR9 signaling could be responsible for the decreased cortico-
steroid responsiveness in SLE patients compared to patients with
other inflammatory diseases.
Administration of TLR7- or TLR9-specific ligands to MRL/lpr mice
accelerates glomerulonephritis [161–164]. Studies in mice deficient
for TLR7 or TLR9 have shown that these receptors play important
roles in the activation not only of pDCs, but also in the activation of
B cells, and in the determination of autoantibody specificities [112].
TLR7 was found to be essential for the production of antibodies
against RNA-containing antigens, such as Sm and Sm-RNP, whereas
TLR9 is required for the production of anti-chromatin and anti-
dsDNA antibodies. However, these receptors had opposite effects on
clinical phenotype, with TLR7-deficient mice demonstrating less
severe renal disease, whereas the absence of TLR9 was associated
with more severe glomerulonephritis. These and subsequent data
suggest that TLR9 has a more complex regulatory role via cross-
regulation of TLR7-dependent processes [165], and mandate some
caution in developing TLR-targeted therapeutic approaches.
Glomerular expression of TLR9 has been detected in the biopsy
samples of some patients with LN, but not in those of controls
[166,167]. There is some disagreement over whether tubulo-
interstitial TLR9 expression is enhanced in LN samples compared to
controls [166–168]. However, sera from SLE patients with anti-
dsDNA reactivity induced the expression of TLR9 in tubular epithelial
cells and tubulointerstitial TLR9 expression was found to correlate
with tubulointerstitial injury [168]. While this suggests an active
role of tubular and possibly glomerular cells in renal inflammation
and tissue damage, the precise mechanisms remain to be elucidated.
3.3.2. T cells in lupus nephritis
MRL/lpr mice with B cells which are capable of expressing surface
Ig, but not of secreting Ig, develop interstitial nephritis, rather than
glomerulonephritis [169]. This suggests the existence of another am-
plification loop in which B lymphocytes act as antigen-presenting
cells in order to activate T cells. As a matter of fact, the tubulo-
interstitial infiltrate in LN biopsy samples frequently contains T- and
179
B-cell aggregates with increasing levels of organization. The highest
level of organization consists of germinal centers with separate B
and T cell compartments around a central network of follicular DCs
[170,171]. Many of these B cells display a mature non-antibody se-
creting phenotype with strong MHC class II expression, suggesting
that they are capable of antigen presentation [170]. This makes it like-
ly that germinal centers contribute to the persistence of renal inflam-
mation. Scattered plasma cells were detected in surrounding areas
[170,171], raising the possibility of in situ autoantibody production,
as has been reported in NZB/W mice, although germinal centers
were not detected in this model [172].
In LN kidney biopsies the mononuclear cell infiltrate is mainly
found in a periglomerular and peritubular interstitial distribution,
and consists primarily of CD3+ T cells, as well as some CD20 + B
cells and macrophages [173–176]. Fewer leukocytes are found within
the glomerulus, where monocytes/macrophages constitute the major
cell type aggregate. The patterns of distribution are quite variable, as
is the CD4 + and CD8 + T cell ratio and its contribution to the total
CD3+ T cell infiltrate, with CD8 + T cells dominating in some sam-
ples and CD4+ T cells in others [173–175,177]. Several studies
found a correlation between the composition of the infiltrate and
the severity of tubulointerstitial inflammation as well as the kidney
damage and the risk of renal failure [174,178,179]. The infiltrating T
cells in LN exhibit a CD28 null memory-effector phenotype, as do uri-
nary CD8 T cells of LN patients [177,180]. Conversely, the proportion
of circulating effector-memory CD8 + T cells was decreased in SLE
patients, particularly those with active renal disease, compared to
healthy controls. This suggests the migration of effector-memory
CD8+ T cells from the peripheral compartment to the kidney [180].
In addition, kidney-infiltrating T cells from LN patients demonstrate
evidence of oligoclonal expansion [177,181,182], specifically CD8+
T lymphocytes [177]. Furthermore, certain expanded clonotypes
were detected in different anatomical regions of the kidney as well
as in the peripheral blood. Certain clones were found to persist and
even expand in patient's biopsy samples taken years apart. In conclu-
sion, these findings strongly argue for an effector function of CD8+ T
cells in the progression of kidney injury.
In the NZM2328 lupus mouse model, the transition from acute to
chronic GN, and the onset of severe proteinuria correspond to the in-
filtration of T cells and CD11 + DCs into the glomeruli, accompanied
by oligoclonal expansion of T cells in the kidney draining lymph
nodes [183]. In LN patients, a decrease in circulating immature pDCs
and certain subsets of mDCs correlates with active renal disease and
is associated with a simultaneous increase of both DC subsets in the
kidney particularly of patients with class III and IV LN [184,185]. DC
accumulation was observed mostly in the glomeruli in one study
[185], but was more pronounced in the tubulointerstitium in another
[184]. This suggests that DC-induced T cell activation may play a sim-
ilar role in driving the progression of renal disease in LN patients.
3.3.3. IL-17 producing T cells
Of the IL-17 group of cytokines, IL-17A and IL-17F are best charac-
terized, and are known to play a central role in adaptive immune re-
sponses to bacteria and fungi. There is also growing evidence of their
implication in the pathogenesis of various autoimmune diseases, like-
ly because of their ability to induce pro-inflammatory responses
[186]. It is generally thought that the major cellular source of these
cytokines is Th17 cells. T cells producing IL-17 are increased in
the peripheral blood of SLE patients in association with marked
upregulation of IL-17 and IL-23 concentrations, the latter being a
cytokine involved in the maintenance of Th17 cells [187,188]. This
was also observed in children with LN. In addition, serum levels of
IL-17 and IL-23 were found to correlate with the SLE disease activity
score, SLEDAI-2K [189]. Peripheral double negative (DN) T cells are
also markedly expanded in subjects with SLE [189,190], and DN T
cells rather than TH17 (CD4+IL-17 +) T cells were found to be the
180 A.T. Borchers et al. / Autoimmunity Reviews 12 (2012) 174–194
major source of IL-17 in these patients [190]. Importantly, both IL-17
and IL-23 were detected in 80% of the LN biopsy samples, mostly in
the tubulointerstitial region. In these biopsies, DN T cells were inter-
spersed with CD4 + and CD8 + T cells. This along with other experi-
mental data implicates the role of IL-17 in the tissue injury of
glomerulonephritis [188,191].
3.4. Genetics
The pathogenesis of SLE involves interactions between environ-
mental and genetic factors [192]. Deficiency of C1q is the strongest
single genetic risk for developing SLE, but is responsible for only a
very small number of SLE cases. It is now recognized that multiple
genes, each making only a small contribution, account for the risk of
developing SLE. Several genome-wide scans have allowed major ad-
vances in the identification of genetic regions predisposing to SLE,
bringing the total number of validated loci to more than 30 [193].
Similar data are not yet available for LN, and most of the association
studies to date have yielded inconsistent results across populations.
Susceptibility to SLE is consistently associated with HLA-DRB1*1501
and HLA-DRB1*0301, particularly in Caucasian populations [193]. An
association of LN with HLA-DRB1*15 has been noted in some studies
[30,193], and an interaction between DRB1*15 and DQA1*01 in
enhancing susceptibility to LN has been suggested, but not yet
confirmed independently [194]. Interestingly, the DRB1*0301 allele
was protective against LN in univariate, but not in multivariate, anal-
ysis in a multiethnic cohort [30]. Among the most consistently identi-
fied associations with SLE are the FCγRI, II and III genes. However, a
recent meta-analyses indicate that the only significant association of
LN with any FCGR polymorphism is seen with the F158 allele of
FCγRIIIA-V/F158 in Asians only, but not in patients of European
or African descent [195]. In contrast, the FCγRIIα-R/H131 and
FCγRIIIβ-NA1/NA2 polymorphisms demonstrate no association with
LN [196,197], whereas data on FCγRIIβ-T/I232 are limited [197].
A variety of candidate genes in the type I IFN pathway have also
been investigated for a possible association with LN, among them,
STAT4 that encodes a transcription factor which is activated by vari-
ous growth factors and cytokines, including IFNα. STAT4 has been
identified as a risk factor for SLE in genome-wide scans in various
populations [193]. An association between a STAT4 haplotype and
LN was seen in two large studies of patients of European ancestry
[198,199], though not in a smaller European study [200]. It also did
not quite reach statistical significance in a cohort of 308 Japanese
SLE patients [201], and was not detectable in a Han Chinese popula-
tion [202]. This suggests that there may be ethnic differences in the
association between STAT4 genotype and SLE phenotype. The risk
variant was found to correlate with higher transcript levels of STAT4
[203] and to enhance sensitivity to IFNα [140], providing biological
plausibility to the genetic association. Note, however, that STAT4
deficiency in experimental animals can reduce or enhance the devel-
opment of glomerulonephritis depending on the precise genetic
background, although autoantibody levels were significantly reduced
in all models [204–206]. A recent genome-wide screen in Han
Chinese identified several novel genetic associations with SLE not
previously identified in European populations [207], of which IKZF1
was found to be particularly associated with LN [208]. This gene
encodes the Ikaros family zinc finger 1 transcription factor, which
has a role in lymphocyte differentiation and proliferation, in part by
targeting STAT4 in T cells.
Interferon regulatory factors (IRFs) are critical regulators of type I
IFN expression in response to TLR engagement, and the subsequent
induction of many type I IFN-regulated genes. In addition, it is in-
creasingly recognized that IRFs have a wide array of other immune
functions. While IRF5 is clearly a risk factor for SLE [207,209], signifi-
cant associations with LN have so far not been detected [199,200].
However, in a Han Chinese population, a strong association was
reported between LN and the IRF7/KIAA1542 region (a polymorphism
in IRF7 is in strong linkage disequilibrium with an SNP in KIAA1542).
Interestingly, these SNPs were not associated with SLE susceptibility
in this population [202], but were identified as a risk factor for SLE in
a European cohort [210].
4. Treatment
4.1. Treatment of class I and II
The type of therapy for LN depends on the severity of renal dis-
ease. Patients with class I and II LN generally have a very good prog-
nosis and rarely require aggressive treatment for their renal disease,
and treatment is guided by other extra-renal SLE manifestations.
However, optimal blood pressure control with angiotensin converting
enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) is
vital. These agents have the added advantage of reducing proteinuria,
and retrospective data suggest that they protect from the develop-
ment of biopsy proven glomerulonephritis [211,212]. Therefore, all
LN patients with proteinuria ≥ 0.5 g/24 h should receive blockade of
the rennin–angiotensin system [213].
4.2. Treatment of class III and IV
Proliferative glomerulonephritis (classes III and IV) represents the
most severe manifestations of renal pathology and requires aggres-
sive immunosuppressive therapy in order to prevent progressive
loss of renal function and minimize associated morbidity and mortal-
ity. Corticosteroids have been the mainstay of every treatment regi-
men for proliferative LN since it was discovered in the 1960s that
high doses (>40 mg prednisone) for prolonged periods of time
(>6 months) can prevent, or at least delay progression to renal fail-
ure [214]. Studies conducted in the 1970s and 1980s by the National
Institutes of Health (NIH) established that the combination of cortico-
steroids with cyclophosphamide (CYC) was superior to therapy with
corticosteroids alone for preserving renal function loss [215–217]. It
was also noted that adding quarterly intravenous (iv) pulse CYC
(ivCYC) to the maintenance regimen of oral corticosteroids for an ad-
ditional two years reduced the rate of LN exacerbations [218]. Similar
to cancer treatment, it is now a custom to distinguish between induc-
tion and maintenance therapy. Induction therapy can be defined as
“a period of intensive therapy with the aim of achieving a clinically
meaningful and sustained response in a patient with active disease”
[219]. The duration of induction therapy is generally individualized
and should be closely monitored for clinically meaningful response.
This depends on disease severity but should last at least 3 months
and should be extended to at least 6 months in cases of persistent
disease activity. The definitions of “clinically meaningful response”
have been highly variable in published randomized controlled trials
(RCTs), making direct comparisons virtually impossible. Hopefully,
future clinical trials adhere to the guidelines proposed by the American
College of Rheumatology (ACR) and the European League Against
Rheumatism (EULAR) [219,220] (summarized in Tables 2 and 3).
Maintenance therapy can be defined as “a period of less intensive
therapy following a period of induction therapy that has achieved a
partial or complete response, with the aim of keeping the patient
free of disease activity.” Note, however, that median time to remis-
sion is approximately 10 months [221–223], meaning it is not
uncommon for meaningful clinical responses to occur only during
maintenance therapy. Therefore, the distinction between induction
and maintenance therapy is somewhat arbitrary except for the
intensity of the therapeutic regimen.
4.2.1. The NIH and Euro-Lupus (ELNT) regimens
The standard regimen developed subsequent to the NIH studies
consists of 6 monthly pulses of ivCYC at a target dose of 0.5–1 g/m 2
 A.T. Borchers et al. / Autoimmunity Reviews 12 (2012) 174–194 181

Table 2
Definitions of partial and complete responses formulated by the American College of Rheumatology (ACR) [220], European League Against Rheumatism (EULAR) [219], and the
Childhood Arthritis and Rheumatology Research Alliance (CARRA) [264].

ACR EULAR CARRA in juvenile LN

Mild response 30–50% improvement in 2 core renal

Improved/partial response/ 25% increase in estimated abnormal
moderate response baseline GFR
≥50% reduction in the urinary protein:
creatinine ratio to a value of 0.2–2.0
Change from active urinary sediment
(>5 RBC/hpf and >5 WBC/hpf and/or ≥1
cellular casts) to inactive sediment
(≤5 RBC/hpf and ≤5 WBC/hpf and no
cellular casts)
Complete response Estimated GFR of ≥90 ml/min/1.73 m2
and ≥50% reduction in the urinary protein:
creatinine ratio to a value of b0.2 and
inactive urinary sediment
Remission
Proteinuria ≤0.5 g/daya
Normal GFR (>90 ml/min) or, if
previously abnormal, improved to a stable
level within 10% of normal GFR
(≥81 ml/min);
Inactive urinary sediment (≤5 RBC or
WBC/hpf [or b10/mm3 or b10/μl]) and no
cellular casts
Proteinuria ≤0.2 g/daya
Normal GFR (>90 ml/min) or, if previously
abnormal, improved to a stable level within
10% of normal GFR (≥81 ml/min);
Inactive urinary sediment (≤5 RBC or WBC/
hpf [or b10/mm3 or b10/μl] and no
cellular casts)
A sustained response of at least 3–6 months,
but it cannot be judged to be a complete
remission in the absence of a biopsy
parameters (proteinuria, renal function as
creatinine clearance or serum creatinine, or
urine sediment) without clinically relevant
worsening of the remaining renal core
parameter
At least 50% improvement in 2 core renal
parameters (with maximum spot protein/
creatinine ratio ≤1.0) without clinically
relevant worsening of the remaining renal
core parameter
Normalization of renal function
Inactive urine sediment (≤5 WBC/hpf,
b5 RBC/hpf, and no casts)
Spot protein/creatinine ratio b 0.2 or age
appropriate

GFR = glomerular filtration rate.

hpf = high power field.
RBC = red blood cell.
WBC = white blood cell.
a
The expert group did not reach an absolute consensus on the values for proteinuria that constituted partial or complete responses, but the values given here reflect the majority
opinion.

body surface followed by pulses at 3-month intervals for 2 years. This is
in combination with 3 initial pulses of iv methylprednisolone, followed
by oral prednisone tapered from an initial dose of 0.5–1 mg/kg to a
maintenance level of 5–10 mg/day [218] (see Table 4). While this
regimen induces remission and preserves renal function in the ma-
jority of the patients, it is also associated with severe and high
rates of adverse events. Specifically, up to 25% of patients experience
major infections [224,225], and herpes zoster occurs in up to 32% of
patients [215,216]. Hemorrhagic cystitis has also been reported
with ivCYC, although much more common in patients on oral CYC
(as many as 17%) [226]. Many physicians routinely add Mesna to
the ivCYC regimen. Up to 60% of women with LN may experience
ovarian failure as a consequence of CYC treatment [215,217]. There
are indications that oral CYC carries a greater risk than ivCYC, possi-
bly due to the higher cumulative dose with oral therapy [215,226].
Both cumulative dose of CYC and age are strong determinants of
sustained amenorrhea, with women past the age of 31 years being
at greatly increased risk [227–229]. Premature ovarian failure is not
only devastating in a patient group that is dominated by young
women in their childbearing years, but also increases the risk of
osteoporosis and cardiovascular disease, a risk that is already
substantially higher in patients with SLE compared to the general
population. The use of gonadotropin releasing hormone analogs dur-
ing ivCYC therapy has been associated with preservation of ovarian
function in the majority of treated patients [230,231]. These findings
await confirmation in larger prospective studies, and the adverse
event profile of such therapy needs to be evaluated. Male SLE fertility
data is limited, but a small study did find that those men treated with
ivCYC had more oligozoospermia, azoospermia and teratozoospermia
than their counterparts [232].
Malignancies, severe leucopenias, and alopecia are other major
concerns with ivCYC therapy. To date, there is no clear evidence
that the efficacy of daily oral CYC differs significantly from that of
pulse ivCYC [215,233]. However, because the studies at the NIH dem-
onstrated an increased risk of hemorrhagic cystitis and premature
ovarian failure with oral CYC therapy [215], the iv route of adminis-
tration is preferred, at least by physicians in North America and
Europe.
The side effect profile of pulse ivCYC and high dose corticosteroid
therapy led to the search of regimens with similar efficacy, but less
toxic. Two approaches have been investigated: lowering the dose of
ivCYC and replacing ivCYC with other immunosuppressants either

Table 3
Definitions of flares formulated by the EULAR [219], and the Childhood Arthritis and Rheumatology Research Alliance (CARRA) [264].

EULAR [219] CARRA in juvenile LN [264]

Flare An increase in disease activity requiring a change of or

increase in therapy
Proteinuric flare Persistent proteinuria > 0.5–1.0 g/day after a complete response A persistent increase in proteinuria to values > 0.5 after
or a doubling of proteinuria, with values higher than 1.0 g/day achieving a complete response or a doubling of proteinuria
after a partial response with values > 1.0 after achieving a partial response
Nephritic flare Increase or recurrence of active urinary sediment (increased Increase or recurrence of active urinary sediment (increased
hematuria with or without reappearance of cellular casts) hematuria with or without reappearance of cellular casts)
with or without a concomitant increase in proteinuria with or without a concomitant increase in proteinuria
Severe nephritic flare Recurrence of active urinary sediment with an increase ≥25%
in serum creatinine
 182
Table 4
Therapeutic regimens in RCTs comparing MMF and/or AZA for induction and/or maintenance to the NIH regimen. Note that all induction regimens are accompanied by oral corticosteroids, which are tapered to a maintenance level of
5–10 mg/day of prednisone or equivalent. The test drug is highlighted by bold print.

Cohort 3 iv MP pulses Induction Maintenance

n WHO class Drug Dose Schedule Duration Drug Dose Remarks Reference

NIH regimen 1 g/m2 ivCYC 0.5–1 g/m2 1 pulse per 6 months ivCYC Quarterly pulses [218]
body surface month for 2 more years
Euro-Lupus (Europe) 46 III, 750 mg ivCYC Max 1.5 g 1 pulse per 6 months ivCYC, then AZA 2 quarterly pulses Initial dose of ivCYC was 0.5 g, [225]
IV, month 2 mg/kg/day increased in 250 mg increments
Vc or AZA was started 2 weeks after the
Vd last ivCYC pulse
44 Low-dose ivCYC 0.5 g/m2 6 biweekly 10 weeks AZA AZA was started 2 weeks after the
pulses last ivCYC pulse
Miami, FL 20 III, 0 ivCYC NIH Up to 7 months ivCYC NIH Patients were switched to [224]
IV or maintenance therapy regardless of
Vb the response to the induction
regimen
20 NIH MMF 0.5–3 g/day
19 NIH AZA 1–3 mg/kg bw/

A.T. Borchers et al. / Autoimmunity Reviews 12 (2012) 174–194

day
MAINTAIN (Europe) 53 III, 750 mg Low-dose ivCYC ELNT 6 biweekly 10 weeks MMF Target 2 g/day Randomization regardless of [258]
IV, (0.5 g/m2) pulses response at 3 months
52 Vc, AZA Target 2 mg/
Vd kg bw/day
a
ALMS (International) 116 III, ivCYC or MMF 24 weeks MMF 2 g/day Randomization only after achieving [259]
IV, or a pre-defined response to induction
V with either ivCYC or MMF
111 AZA 2 mg/kg bw/day
b
ALMS (International) 185 III, ivCYC NIH 1 pulse per 24 weeks [241]
IV, or month
185 V MMF Target 3 g/day 1.5 g, 24 weeks MMF was titrated from 1 g daily in
2× per day week 1, to 2 g daily in week 2, and to
3 g daily in week 3
US multicenter 69 III 0 ivCYC 24 weeks [242]
71 IV, or MMF Maximum 1 g, 24 weeks MMF was titrated from 1 g daily in
V 3 g/day 3× per day week 1, to 1.5 g daily in week 2, to a
maximum of 3 g daily thereafter
Malaysia multicenter 25 III, or 0 ivCYC 0.75–1 g/m2 1 pulse per 6 months [240]
IV month
19 MMF 2 g/day 1 g, 2× per day 6 months
Nanjing, China 23 IV 0.5–1 g ivCYC 0.75–1 g/m2 1 pulse per 6 months [239]
month
23 0 MMF 1–1.5 g/day 0.5–0.75 g, The dose of MMF was reduced to
2× per day 0.5–1 g/day after 3–6 months
depending on disease activity
DLNS (the Netherlands) 50 III 0 ivCYC 0.75 g/m2 1 pulse per 6 months ivCYC; followed by AZA 7 quarterly [252]
IV month pulses; 2 mg/kg/
Vc or day
37 Vd 1g AZA+MP 2 mg/kg/ AZA daily; AZA 2 mg/kg/day
day+ 1 g/day additional 3
iv MP daily Methyl
prednisone
pulses at weeks
2 and 6
Hong Kong 31 IV 0 Oral CYC 2.5 mg/kg/day daily 6 months AZA 1.5–2 mg/kg/day [247]
33 MMF 2 g/day 1 g, 2× per day MMF or AZA See remarks MMF dose was originally halved
after 6 months and replaced by AZA
after 12 months; later, patients re-
ceived 1.5 g/day for 6 months and
1 g/day for an additional 12 months
before being switched to AZA
 A.T. Borchers et al. / Autoimmunity Reviews 12 (2012) 174–194
during maintenance alone or during induction and maintenance —
always in conjunction with glucocorticoids. The Euro-Lupus Nephritis
Trial investigated whether the dose of ivCYC used as induction thera-
py could be lowered without losing efficacy [225] (see also Table 4).
Of note, another major departure from the NIH regimen in this trial
was the use of azathioprine (AZA) for maintenance in both treatment
arms. However, at the time the trial was designed (recruitment began
in 1996), there had been no published randomized controlled trials
establishing the equivalence of AZA and CYC in maintenance therapy,
even though AZA had been in clinical use for some time [234]. After a
median of 41 months of follow-up, there were no significant differ-
ences between the two treatment arms in terms of the rates of treat-
ment failure, remissions and flares. Infections were twice as frequent
in the high dose compared to the low dose group, but this did not
reach statistical significance [225]. Similar results were reported
after the 73 months of follow-up, with renal functional impairment
being observed at similar rates in the two groups [235]. At ten
years, still no significant difference between the two treatment
regimens could be observed, with regards to death, end-stage renal
disease (ESRD), and sustained doubling of serum creatinine occurring
at similar rates [236]. When channeling these studies to clinical prac-
tice, one needs to take into consideration that the vast majority of
the patients enrolled were of European ancestry; therefore, it may
not be appropriate to extrapolate these findings to other patient
populations. Early data from a small prospective controlled study
suggest that the NIH and the ELNT regimens are equally effective in
Egyptian patients [237].
4.2.2. Mycophenolate mofetil (MMF) as induction therapy
The results of several small Asian studies demonstrate that the
efficacy of MMF as induction treatment is similar to that of ivCYC
[238–240]. However, a large international multi-center trial designed
to demonstrate the superiority of MMF failed to do so [241]. In con-
trast, a US multicenter non-inferiority trial actually demonstrated
the superiority of MMF compared to ivCYC as an induction therapy
since the rates of complete remission were significantly higher in
patients receiving MMF [242]. The frequency of infections in general
and severe infections in particular was similar in two studies
[240,241], but higher in the ivCYC-arm induction compared to MMF
in another RCT [242]. Leucopenia appears to be somewhat more fre-
quent with ivCYC than with MMF [239,242]. Divergent results have
been reported on gastrointestinal side effects, with some studies
reporting a similar incidence of nausea and vomiting during ivCYC
and MMF treatment [240,242], whereas others found these distur-
bances to be significantly more frequent in patients treated with
MMF [241]. Diarrhea was markedly more frequent during induction
therapy with MMF [241,242].
Some of these discrepancies in the results for both the efficacy and
toxicity of MMF compared to ivCYC may stem from the different eth-
nic distributions of the study participants. The US multicenter study
included a high proportion of African-American as well as Hispanic
population, but fewer Asian patients [242], whereas the international
study included ~ 40% European, 33% Asian, and 27% “other” patients
[241]. There is growing evidence that African American and Hispanic
patients have poorer responses to ivCYC compared to patients of
European ancestry [243,244]. The most striking differences came
from the international trial itself, where ivCYC was significantly less
Notes to Table 4
ALMS = Aspreva Lupus Management Study; DLNS = Dutch Lupus Nephritis Study; NIH = National Institutes of Health; MP = methylprednisolone.
AZA = azathioprine.
CYC = cyclophosphamide.IV = intravenous.
MMF = mycophenolate mofetil.
RTC = Randomized controlled trials.
a
See the study by Appel et al. [241] below.
b
This study purports to have followed the NIH protocol as described by Boumpas et al. [218], but does not mention the 3 iv methylprednisolone pulses that are part of this
protocol.
183
effective compared to MMF in patients whose ethnicity was classified
as “other” (mostly of African, Mexican-mestizo and mixed ancestry)
[241]. Post hoc analyses revealed that Hispanics also had a higher
response rate to MMF compared to ivCYC, and that more patients of
African descent receiving ivCYC withdrew because of adverse events
compared to those receiving MMF. Opposite results were observed
for patients of European and Asian ancestry [241,245]. Interestingly,
Asians tolerated MMF more poorly and withdrew more frequently
due to its adverse events compared to other racial groups. Thai pa-
tients with LN were found to have low oral clearance of the active
metabolite of MMF [246], suggesting a possible explanation for this
excess toxicity. Of note, the target dose of MMF was 3 g/day (in divided
doses) in this international RCT and the median dose was 2.6 g/day
[241], whereas earlier studies in Asian populations used as little as
1–1.5 g/day in China and 2 g/day in Hong Kong and Malaysia with
remarkable efficacy and few discontinuations because of adverse events
[239,240,247]. Even doses of 0.5–1 g/day were reported to induce clin-
ically meaningful responses in Taiwanese patients with class III-V LN
[248]. Recent data from China indicate that MMF at a dose of 0.75–1 g
twice daily is significantly more effective and less toxic than ivCYC
even in the most severe forms of LN, namely class IV LN with
non-inflammatory necrotizing vasculopathy [249], and in crescentic
LN (ISN/RPS class IV or class IV+ V with crescent formation affecting
>50% of glomeruli) [250]. Interestingly, although the actual drug cost
of MMF is considerably higher compared to ivCYC, the results of a
patient-level simulation model suggest that induction therapy with
MMF is actually less expensive compared to ivCYC. This is probably
due to the additional costs for the procedures and facilities that are nec-
essary for iv drug administration and the additional cost of antiemetics
and Mesna as well as the higher rate of major infections with ivCYC
compared to MMF [251].
4.2.3. AZA plus methylprednisolone for induction
A Dutch RCT compared an induction treatment with 6 pulses of
ivCYC to a combination of AZA at 2 mg/kg/day plus iv pulses of 1 g/d
of methylprednisolone for 3 days at week 0, 2 and 6, both regimens
being combined with oral prednisone [252] (see also Table 4). Both
groups received AZA plus prednisone after 2 years. During the first
two years of treatment, there was no significant difference in the cumu-
lative incidence of partial or complete renal remission. However, repeat
biopsies obtained after 2 years from a subset of participants in this trial
demonstrated that the chronicity score increased significantly more in
the AZA group compared to ivCYC; the activity index decreased to the
same extent in both groups [253]. After extended follow-up (up to a
median of 9.6 years), relapses were significantly more frequent in the
AZA group, and sustained doubling of serum creatinine demonstrated
a similar trend [252,254]. There were no significant differences in mor-
tality or development of ESRD. During the first 6 months of treatment,
infections (particularly herpes zoster) were more frequent in the AZA
arm. This may have been due to the higher steroid dose in this group.
In a prospective assessment of participants in this RCT, health-related
quality of life (HRQoL) improved in both groups, particularly during
the first year, with only minor differences between the two treatment
arms [255]. The mean treatment burden, assessed on a 5-point Likert
scale, was significantly higher in the CYC group at 24 months. Unfortu-
nately, studies comparing HRQoL during other treatment regimens
184 A.T. Borchers et al. / Autoimmunity Reviews 12 (2012) 174–194
have been based on recall several years after treatment, making their
results rather questionable [256,257].
4.2.4. MMF or AZA for maintenance
A single-center study compared quarterly pulses of ivCYC, MMF
and AZA for maintenance therapy, patients receiving MMF had a mar-
ginally higher probability of survival (p = 0.11), a lower rate of the
composite endpoint of death or ESRD (p = 0.05) and were significant-
ly more likely to remain free of relapses compared to patients treated
with quarterly pulses of ivCYC [224]. The results were similar for the
AZA group, except that the difference in overall survival and
event-free survival (i.e., free of death or ESRD) compared to ivCYC
achieved statistical significance (p = .02 and .009, respectively),
while relapse-free survival was only marginally better (p = 0.12).
The rate of hospitalizations, the frequency of infections overall and
of major infections, and the incidence of sustained amenorrhea
were all significantly higher in the ivCYC compared to the other
groups, and nausea and vomiting were also more frequent.
Direct comparisons between AZA and MMF as maintenance thera-
py have yielded somewhat inconsistent results. In a predominantly
European patient group, the two treatment modalities resulted in
very similar outcomes (time to renal flare, severe systemic flare, or
renal remission) [258]. The frequency of adverse events in general
as well as individual adverse events did not differ significantly be-
tween the two groups except for leucopenias and other cytopenias,
which were more frequent during AZA treatment. In contrast, others
found MMF to be superior to AZA in terms of time to treatment failure
overall and individual components of this outcome measure, i.e., time
to renal flare and time to rescue therapy [259]. Serious adverse events
tended to be more common in the AZA group, and the frequency
of withdrawals due to adverse events was significantly higher in
the AZA group. The trials differed in their induction regimens
(Euro-Lupus vs. NIH or MMF) and in the requirement for a response
to induction before randomization (see Table 4 for details). In addition,
the second study included 33.5% Asian patients, 43.6% of European
ancestry, 10% black and 13% other [259]. It is difficult to determine
to what extent these differences contributed to the outcome disparities.
It is customary to adjust the dose of ivCYC according to the white
blood cell nadir 7–10 days after an infusion, with the minimum value
requiring a dose reduction of 25% varying between 1500 and
3500 cells/μl in different studies [218,224,240,252]. In contrast,
there is no suggested dose adjustment regimen with MMF. Several
studies in patients with SLE, including mostly subjects with LN, have
shown that there is up to 10-fold inter-subject variability in indi-
vidual plasma concentrations of mycophenolic acid (MPA), the active
metabolite of MMF [246,260–263]. In analogy to the use of pharmaco-
kinetic parameters for individualizing doses of MPA in transplant
recipients, a Bayesian estimator of the area under the curve from
0 to 12 h (AUC0-12) of plasma MPA concentration has been derived
for determining MPA exposure in SLE patients [260]. The resulting
AUC0-12 estimate was found to correlate inversely with disease
activity as assessed by SLEDAI or BILAG [261]. Based on this, an
AUC0-12 of ≥ 35 mg h/l was identified as the target value above
which active SLE becomes rather unlikely (negative predictive value
of 92%). In a pilot study in patients with childhood-onset LN, a similar
value was identified (>30 mg h/l) [263]. Most available data is on
French and US patients, including a considerable portion of patients
with African ancestry, but few Asian subjects.
Various “meta-analyses” on the efficacy of MMF compared to CYC
or AZA have been published, but have serious limitations. 1) They do
not take into account that almost every one of the clinical trials with
MMF used different definitions for outcome measures (e.g., partial or
complete remission, improvement, relapse). 2) The duration of
follow-up was highly variable [215,252]. The ACR now recommends
a minimum trial duration “of 6 months, better 1 year, and ideally
5 years” [220]. 3) The proportion of newly diagnosed patients in
existing clinical trials was highly variable and not always specified.
Yet, it seems quite likely that patients who did not respond to other
therapeutic modalities or who initially responded but relapsed differ
from patients who are treatment-naïve. 4) The existing meta-
analyses do not take the ethnic composition of the patient groups
into account, a factor that has been shown to influence treatment
responses [241,243–245].
The ACR recently published new guidelines for the treatment of
LN [213].
For class III and IV LN, the Task Force Panel recommends an initial
three daily pulses of iv glucocorticoids (500–1000 mg). It considers
ivCYC and MMF as equivalent for induction therapy, but recommends
the use of MMF as the first line agent in African American and Hispanic
patients. For Asians, the total daily dose of MMF should not exceed 2 g,
whereas a target dose of 3 g/day is recommended for non-Asians. The
use of ivCYC following the ELNT protocol should be reserved for patients
of predominantly European descent. People not responding to induc-
tion with ivCYC or MMF after 6 months should be switched to
the other agent. While the Task Force Panel does not recommend AZA
for induction, it considers AZA and MMF essentially equivalent for
maintenance therapy; ivCYC is no longer considered an option for
maintenance. The ACR guidelines specifically point out that there
currently is inadequate data to guide physicians as to when and how
to taper or withdraw AZA or MMF.
Importantly, while MMF and CYC are teratogenic, AZA is associated
with a relatively low risk of fetal abnormalities and can be used as a
steroid-sparing agent for active LN during pregnancy. Childhood-onset
LN is not given special consideration in the ACR guidelines, even though
the benefits of immunosuppressive therapies need to be weighed even
more carefully against their toxicities in the context of the increased
vulnerability of a growing organism. Nonetheless, a recent survey
revealed that members of the Childhood Arthritis and Rheumatology
Research Alliance most commonly used the NIH regimen of ivCYC for
induction in patients with juvenile-onset LN [264]. It would seem advis-
able, however, to consider the Euro-Lupus regimen in order to minimize
drug-induced morbidity. A modified version of this regimen (6 monthly
rather than biweekly pulses of 500 mg/m2 of ivCYC) followed by AZA,
or MMF if not responsive to AZA. Good results have been reported
with this regimen in Turkish children with class III or IV LN, although
a comparison group is unfortunately missing [265]. Data are beginning
to emerge demonstrating that tacrolimus may be as effective as ivCYC
for induction therapy in proliferative LN [266], while cyclosporine A
demonstrated similar efficacy as AZA in reducing proteinuria and pre-
serving renal function during maintenance therapy [267]. The adverse
event profile was more favorable with tacrolimus and cyclosporine A
compared to ivCYC and AZA, respectively. Further studies are in prog-
ress with these agents as single therapy or in combination with MMF.
However, these agents are not included in the ACR Task Force recom-
mendations, likely because of insufficient evidence at this time.
Several studies found that hydroxychloroquine decreases the risk of
progression to ESRD and mortality rate [268–270]. This is consistent
with the ability of antimalarials to enhance the response to immuno-
suppressive therapy with MMF, reduce the frequency of flares and
limit damage accrual, including renal damage [271–274]. Consequently,
the ACR treatment guidelines recommend adding hydroxychloroquine
to the regimen of all SLE patients with LN [213].
4.3. Treatment of membranous LN
Class V or membranous LN (MLN) often occurs in combination with
proliferative lesions in which case it requires the same treatment as for
class III or IV lesions. Therapy of pure MLN remains somewhat contro-
versial, because renal functional decline is slower compared to class III
or IV LN and the long-term prognosis is felt to be more favorable. That
being said, MLN is often accompanied by nephrotic-range proteinuria,
which increases the risk of thromboembolic and cardiovascular
 A.T. Borchers et al. / Autoimmunity Reviews 12 (2012) 174–194
complications. Corticosteroids represent the mainstay of therapy in
membranous LN, even though their benefit has not been clearly
established. It is generally agreed that patients with high-grade protein-
uria require the addition of other immunosuppresants to corticoste-
roids. Unfortunately, RCTs in patients with pure MLN are rare. There
are indications that induction and maintenance with ivCYC, MMF, and
AZA are effective in MLN [275,276], but cyclosporine A, tacrolimus, or
chlorambucil may be similarly beneficial and less toxic [277–279].
Therefore the potential risks and benefits of each of these treat-
ments must be carefully weighed in each individual patient. The ACR
recommends a combination of prednisone (0.5 mg/kg/day) and MMF
(2–3 g/day) for induction in patients with pure class V nephritis and
nephrotic-range proteinuria [213].
4.4. Biological agents as further treatment options
4.4.1. Belimumab
Belimumab represents the first new drug approved for treatment of
SLE in decades both by the Food and Drug Administration (FDA) and by
the European Medicines Agency. It is a fully human monoclonal anti-
body against B lymphocyte stimulator (BLyS), also known as B cell acti-
vating factor (BAFF), a cytokine that provides survival signals for B cells
and is overexpressed in patients with SLE. Inhibition of BLyS with
belimumab results in reductions in subsets of circulating CD20+ B
lymphocytes and short-lived plasma cells. Two phase III trials of
belimumab in addition to stable treatment with prednisone, anti-
malarials, or other immunosuppressants (but not ivCYC) in the treat-
ment of patients with active SLE demonstrated it to be effective in
reducing disease activity and severe flares [280,281]. Patients with
severe active LN were specifically excluded from both trials, but signif-
icant effects on normalization of anti-dsDNA antibodies and low com-
plement levels suggest that belimumab may also be beneficial in LN.
Post-hoc analysis of the few patients with proteinuria > 2 g/24 h indi-
cated that the proportion dropped from 9% and 7% to 5.5% and 4.2% in
the groups treated with 1 and 10 mg/kg belimumab, respectively.
Comparison with the placebo group (7.6% proteinuria> 2 g/24 h) did
not meet statistically significant differences. However, there was a
significant reduction in the frequency of renal flares and a tendency
for greater reduction in proteinuria.
4.4.2. Rituximab and ocrelizumab
Rituximab is a chimeric monoclonal antibody to CD20, which
depletes B lymphocyte precursors and mature B cells because they
express CD20 on their cell surface. A phase III trial examined the
effects of treatment with rituximab on days 1, 15, 168, and 182 com-
pared to placebo, both in combination with MMF, in patients with
newly diagnosed LN [282]. The response rate was small and did not
meet statistical significance. While rituximab may not be more effec-
tive than standard care with immunosuppressive agents as first line
therapy, open label evidence suggests that rituximab has a place
in the treatment of patients with refractory disease [283–285].
According to a pooled data analysis from 164 patients with LN, most
of whom refractory to treatment, 27% of these patients achieved a
complete response with rituximab [284]. It appeared particularly
effective in patients with mixed membranous-proliferative LN and
type III LN (with complete response rates of 75% and 48%, respective-
ly, compared to 27% in type V and 16% in type IV LN). Keeping the
rituximab risk profile in mind, there have been at least 3 reported
cases of progressive multifocal leukoencephalopathy (PML), a gener-
ally fatal demyelinating disease, in patients with rheumatoid arthritis,
and 2 reported cases in SLE patients with post treatment. Patients
with SLE and possibly other connective tissue diseases, but not with
rheumatoid arthritis, have an increased risk of PML even in the ab-
sence of biological therapy [286]. The FDA has issued a public health
advisory on this issue. The ACR treatment guidelines state that
rituximab can be used in patients refractory to induction therapy
185
with MMF or ivCYC [213]. A phase III clinical trial investigating the
treatment of LN with the fully humanized anti-CD20 monoclonal
antibody ocrelizumab in addition to corticosteroids and MMF or
ivCYC is ongoing (www.clinicaltrials.gov).
4.4.3. Abatacept and other biologicals
Abatacept is a soluble Fc:CTLA-4 fusion protein that prevents T cell
activation by competing with CD28 for binding to CD80/86, a
costimulatory signal required for full T cell activation. In the first
double-blind RCT of abatacept, none of the primary or secondary end-
points were met [287]. Patients with LN were specifically excluded
from this trial. A phase II/III study of abatacept (plus MMF and corti-
costeroids) was terminated due to inefficacy in the short-term
phase (www.clinicaltrials.gov). Another phase two trial is ongoing.
Overall the data are disappointing [288]. Trials with other biological
agents, such as epratuzumab, atacicept, and abetimus have either ex-
cluded patients with LN, failed to demonstrate effectiveness, or are
still ongoing. TNF antagonists or IL-1 blockade is not advisable in pa-
tients with LN [285].
5. Biomarkers
It would be of great help to use biomarkers that could obviate the
need for biopsies, in particular repeat biopsies, in order to assess LN
activity or kidney damage, and that could accurately predict an immi-
nent exacerbation of renal disease [289,290]. The usual marker of
renal disease is urinary protein, but the currently recommended
spot urinary protein to creatinine ratio may not be sufficiently sensi-
tive to detect early nephritis [220,291]. Conventional markers of ac-
tive renal disease are serum levels of anti-dsDNA, anti-C1q antibody
and complement levels. However, these have widely variable sensi-
tivity depending on the assay system used, and their specificity
ranges between 50 and 75% for active renal disease [291,292]. Al-
though both serum and urinary compounds have been investigated
for their potential use as biomarkers, it is generally felt that urinary
substances are likely to reflect kidney damage better. Urinary candi-
dates have included adhesion molecules, cytokines, chemokines,
and their receptors, including VCAM-1, P-selectin, IL-6, IP-10,
RANTES, MCP-1, CXCL16, CX3CL1, TWEAK, and TNFR1 [98,291]. In
addition, proteomic approaches have identified a variety of other uri-
nary proteins that are associated with LN, including transferrin, ceru-
loplasmin, hepcidin 20, hepcidin 25, α1-acid-glycoprotein, lipocalin-
type prostaglandin D-synthetase, and neutrophil gelatinase associated
lipocalin. In particular, the second group of proteins (non-immune
related) contains some of the most promising candidates for
predicting renal flares [293,294]. However, the current results await
independent confirmation in large scale prospective studies. In addi-
tion, it is unlikely that a single biomarker will have sufficient sensitiv-
ity and specificity for the diagnosis, activity, response to treatment, or
prognosis of LN. Therefore, future research should focus on the utility
of different biomarker combinations to evaluate active renal disease
or to provide prognostic information.
6. Outcome/prognosis
6.1. Remission and flares
A major outcome measure in clinical trials and observational stud-
ies has been the achievement of “remission.” It should be noted, how-
ever, that the terms “major clinical response” or “partial clinical
response” are preferable since true remission can only be established
by a follow-up biopsy, which is not routinely performed [295]. None-
theless, we use the terms interchangeably in this review. In clinical
trials, approximately 50% of patients with proliferative LN experience
a clinically meaningful response within 6 months, although complete
responses are quite rare during induction therapy [239–242]. The
186 A.T. Borchers et al. / Autoimmunity Reviews 12 (2012) 174–194
proportion of patients who eventually reach partial or complete re-
mission ranges from ~ 60 to 90% in clinical trials and observational
studies [224,225,247,252,259]. Similar response rates have been
reported in patients with membranous LN [296,297], with the excep-
tion of a Spanish cohort, where only 32% of patients with class V LN
achieved remission compared to 78% and 70% of patients with class
III and class IV lesions, respectively [268]. Much of the variability
between studies is attributable to the use of different definitions of
remission, but also to different patient characteristics and treatment
regimens. Median time to remission in patients with proliferative
GN treated with ivCYC is approximately 10 months [221–223],
although markedly shorter response times have been reported [247].
Kidney disease relapse even in a patient who achieved a complete
clinical response is common. Unfortunately, relapse rates are often
reported as the proportion of patients experiencing a renal flare,
which makes comparison difficult due to varying lengths of follow-
up. However, it seems that at least 40% of patients with proliferative
GN will eventually have a flair [222,223,298,299], and only slightly
lower rates have been reported in MLN [296,297,300]. Median times
to renal flare range from 32 to 79 months [222,298,299]. The induc-
tion of re-remission after a renal exacerbation is more difficult and
successful in only about two-thirds of the patients [222]. Those who
fail to achieve a second remission are at increased risk of progressing
to renal insufficiency or ESRD [222,298,299]. Predictors of renal flares
include failure to achieve a complete response [223,299], persistence
of low complement levels after treatment [298,299], longer time to
remission [222], longer delay before the initiation of treatment
[223], and African ancestry [298].
6.2. Progression to ESRD
Although more treatment options have become available for LN
over the last decades, analysis of data from the US Renal Data System
revealed a steady increase in the rate of ESRD due to LN between
1982 and 1995 [301] and a subsequent stabilization, but no decline,
of this rate in the years 1996–2004 [302]. A study using the same
data source, but adjusting more thoroughly for annual population
changes and also investigating changes by US region, found that the
incidence of ESRD actually rose in patients aged 5–39 years old, in
African Americans and Native Americans, and in the southern US
between 1995 and 2006 [303]. That being said, this trend may actual-
ly reflect increased survival rates in SLE patients. It may also be due to
changes in the SLE epidemiology in general and/or the proportion of
SLE patients with LN, but unfortunately, recent population-based
incidence data are not available for the US. Importantly, survival dur-
ing the first 3 years of ESRD did not improve between 1995 and 2006
[303]. Comparisons of patient groups diagnosed and treated at the
same institutions during different periods also demonstrate that the
rate of ESRD has not changed significantly over the last 30 years
[304–306]. The time from ESRD to death increased only slightly and
non-significantly [304]. However, in one of these cohorts, patients
with proliferative LN diagnosed between 1987 and 2000 faced a
significantly lower risk of doubling serum creatinine compared to
patients diagnosed between 1973 and 1986 [306]. Some recent
renal survival rates are summarized in Table 5.
It is amply documented that SLE patients from most non-European
populations develop renal involvement more frequently than patients
of European descent, are more often treatment resistant (at least to
ivCYC) and face a considerably poorer prognosis, i.e., develop renal
insufficiency and ESRD far more frequently and are at increased risk of
death [11,29,243,307–309]. There have been numerous attempts to
determine whether this is due to socioeconomic, sociocultural or
other factors, but the results have been controversial. Several analyses
demonstrate African ancestry to be an independent risk factor for
poor renal outcome [243,310,311], and this includes patients with
juvenile-onset LN [312]. Other studies, however, found it to be
significant in univariate analysis only and to lose significance once
poverty, insurance status, various clinical factors, and non-compliance
were isolated [28,313–318]. In some multivariate analysis, Hispanic
ethnicity was identified as a risk factor for doubling serum creatinine
and progression to ESRD [28,314]. In contrast, Hispanic children in
Florida were significantly less likely to progress to ESRD [312]. This
underscores again the heterogeneity of “Hispanic” populations [29].
Overall, it seems likely that both socioeconomic status and “ethnicity”
represent genetic as well as socio-cultural factors and contribute to
the worse outcome of LN in African-American and other non-
European populations. Of note, in a predominantly African-American
and Hispanic cohort of pediatric patients with LN, the introduction of
MMF into the standard therapeutic regimen was associated with signif-
icant improvement in 5-year renal survival from 52% to 91% [312]. This
may be attributable to the superior efficacy of MMF in these populations
[241,245].
A long list of other demographic, clinical, and histopathological risk
factors for poor renal outcomes has been identified. Given the heteroge-
neity of the disease itself, the investigated populations, and the treat-
ment regimens, it is not surprising that the results have been
inconsistent. As expected though, treatment resistance has been identi-
fied as an independent predictor of ESRD in numerous cohorts
[55,223,226,309,316,319], including patients with MLN [296,300].
Demonstrating a response within 6 months of initiation of therapy
may be a particularly important predictor for good long-term outcome
[235,236]. A renal flare represents new tissue injury and is likely to
result in renal cell death and fibrosis, leading to loss of glomerular and
tubular function. Therefore, an association between renal relapses and
progression to ESRD is to be expected and has been found in several
studies of patients with both proliferative and membranous nephritis
[300,306,309,320], although statistical significance is not always
retained in multivariate analysis [296,299]. Hypertension is commonly
found to predict progression to ESRD [305,313,321–324], and decreased
renal function at baseline is another frequently identified risk factor for
poor renal outcome [55,223,268,300,305,313,321–326]. Diagnostic
delay is also an important predictor of ESRD [327–329]. This suggests
that responsiveness to therapy may be decreased once renal function
has begun to deteriorate, possibly due to delayed diagnosis of LN and
progressive tissue damage. This is supported by the finding that a
lower chronicity score for renal biopsy samples predict better response
to treatment (with ivCYC) [60,226]. In addition, a significant indepen-
dent association has been detected between the chronicity index of
tubulointerstitial disease and progression to ESRD [178,179,300,305,
306,313,321,330]. Interestingly, class IV LN, which is generally thought
to carry the greatest risk of progression to ESRD, is not consistently
identified as an independent predictor of renal failure [56,305,322–
324,327,331].
6.3. Renal replacement therapy treatment
Once a patient with LN has progressed to ESRD, the initial choices
for renal replacement therapy include preemptive kidney transplan-
tation, peritoneal dialysis, or hemodialysis. Preemptive kidney trans-
plantation carries a better graft and patient survival in recipients with
LN compared to dialysis treatment prior to transplantation [332].
Compared with hemodialysis replacement therapy, peritoneal dialy-
sis prior to transplantation is associated with better allograft survival,
particularly in LN patients [333]. However, pediatric SLE patients who
are treated with peritoneal dialysis prior to kidney transplant have a
significantly higher rate of early graft failure than patients who
were treated with hemodialysis [334].
In the US, the initial choice of renal replacement therapy for
patients with ESRD due to LN is strongly influenced by socio-
demographic factors, insurance status, and employment status
[335], although this does not appear to differ greatly from the experi-
ence of patients with ESRD due to other causes [336]. Patients of
 A.T. Borchers et al. / Autoimmunity Reviews 12 (2012) 174–194 187

Table 5
Patient and renal survival.

Study location Study period n Classes Patient survival Renal survival Reference

5-year 10-year 15-year 20-year 5-year 10-year 15-year 20-year

Adults Barcelona, Spain 1970–2006 190 II–VI 92 80 [268]

Hong Kong 1968–2008 230 I–V 98.6 98.2 90.5 99.5a 98 89.7 [344]
Hong Kong 1988–2002 268 IV 88.7 82.8 70.7 [226]
Hong Kong 1976–1997 183 I–V 98.9 94.4 94.4 92.1 81.2 75.2 [368]
Copenhagen, Denmark 1971–1995 100 II–V 87 83 73 [305]
Zhenzhou, China 2003–2010 491 I–VI 88 77 53 45 [269]
Lucknow, India 1988–2007 188 II–VI 91 81 76 [323]
Riyadh, Saudi Arabia 1980–2006 299 I–VI 96 95 [324]
Italy 1974–2008 67 V (pure) 97.5 94.5 96.5 85.8 83 [300]
Nanjing, China 1986–2004 100 V 98 98 96.1 92.7 [296]
Children Taiwan 1979–1991 167 II–V 91.1 93.1a [369]
Serbia and Montenegro 1983–2001 53 I–V 98.1 88.6 [346]
Egypt ??–2007 100 II–V 82.4 64.7 [18]
India 1985–2007 180 I–V 77 65 53 92a 91a 79a [331]
a
Renal survival was calculated only for patients alive at the time of analysis.

African, Asian or Hispanic descent were found to be less likely to
receive preemptive kidney transplants [335]. In addition, African
Americans, Medicaid recipients and unemployed patients received
peritoneal dialysis less frequently compared to Americans of European
descent, privately insured and employed patients. Patients receiving
hemodialysis for ESRD secondary to LN are at increased risk of death
compared to patients with ESRD due to other causes [337]. In particular
the mortality risk for pediatric patients was found to be 2.4-fold higher
compared to other children with ESRD. The risk of death while on
hemodialysis was found to be markedly higher for African American
children with ESRD due to LN [338]. In addition, African American and
Hispanic patients with childhood-onset LN and ESRD had 50% and 37%
lower 5-year survival rates of kidney transplantation compared to
other populations even after adjusting for US region and medical insur-
ance, which were also significantly associated with the rate of kidney
transplantation.
Most large-scale studies demonstrate equivalent renal and patient
survival in patients with ESRD due to LN compared to patients with
ESRD due to other causes [339,340], and limited data suggest that
the same is true for adult patients with childhood onset of LN [334].
African-American transplant recipients, but not Hispanic recipients,
were at significantly increased risk of graft failure, but not of death,
in a multivariate analysis of data from the US Renal Data System be-
tween 1995 and 2002 [333]. Possible explanations for higher preva-
lence of allograft failure in African American transplant recipients
are higher rates of cadaveric allograft, a higher percentage of two
HLA loci mismatches, experiencing more delayed graft function, and
more early rather than late rejection episodes [341,342]. In LN
renal allograft recipients, recurrence of LN is seen in about 2–30%
[341–343]. It is generally mild (most often mesangial, less frequently
membranous, and rarely proliferative), and was found to be a risk fac-
tor for allograft loss, but does not significantly affect patient survival
[342]. The only significant risk factor for LN recurrence identified in
a multivariate analysis was African-American ancestry [342].
6.4. Patient survival
Starting in the 1950s, the survival of SLE patients overall increased
from less than 50% to >95% at 5 years post diagnosis in industrialized
areas [6]. Nonetheless, the standardized mortality ratio (SMR) gener-
ally remains ≥ 2, even if survival of lupus patients approaches that of
the general population in some regions [7]. Although the risk of death
from renal disease has decreased substantially over the last decades,
mortality remains significantly higher among patients with LN com-
pared to patients with SLE overall [7]. The SMR (reflecting all causes
of death rather than renal disease alone) was 5.9 for patients with
proliferative LN who were followed in Hong Kong between 1968
and 2008 [344], and 6.8 for a Danish cohort with all classes of LN
followed from 1971 to 1995 [305]. Importantly, both studies found
that the SMRs had not changed significantly at least since the begin-
ning of the 1980s [305,344], confirming the findings of an earlier
study [345], although others found that survival improved into the
1990s and then stabilized [304]. Five-year survival rates > 98% have
been reported in adult and pediatric cohorts of patients with LN
[344,346], although it is not always clear whether diagnosis of SLE
or LN represents the starting point of the analysis. However, survival
rates remain markedly lower in developing countries, particularly in
pediatric cohorts (see also Table 5). The difference becomes more
pronounced with longer follow-up, with recently reported 10-year
survival rates ranging from 68% to 98.2% [9,344,347].
In a cohort from Hong Kong, the SMR for patients who developed
ESRD was 26.1, even though ESRD was the immediate cause of death
in only one of the 24 patients who died [344]. However, chronic as
well as acute renal failure remains an important cause of death for pa-
tients with LN in developing countries [9,324,331]. Generally infec-
tions represent the leading cause of death in adult and pediatric
patients with LN in industrialized and developing countries around
the world [226,268,269,312,323,324,344]. This is most likely due to
the long-term use of immunosuppressive therapies in these patients.
Cardiovascular and cerebrovascular disease accounts for about
15–30% of all deaths in patients with LN, reflecting the increased
risk of cardiovascular complications in patients with SLE overall, as
well as the combined harmful effects of renal failure and chronic
corticosteroid therapy [226,268,269,312,344]. Treatment with CYC is
known to increase the risk of malignancies, and these are responsible
for approximately 10% of deaths in LN cohorts [226,268,344].
6.5. Future directions
It is clear that there remains a major void in the successful man-
agement of lupus nephritis. On the other hand, the strides in the
basic biology of lupus in both humans and mice have been striking.
Examples of basic observations that need eventually to be translated
into clinical therapeutics include detailed understandings of regulato-
ry T cells, the correlation, if any, between the multiple variants of mu-
rine lupus and human disease, the increasing interest in epigenetics,
the role of environmental agents, including drugs, in disease induc-
tion, methodology to alter complement activation in kidneys, defini-
tion of the critical roles of toll-like receptors, a better understanding
of hematopoietic precursors and their role in loss of tolerance, more
aggressive use of genomics, study of critical populations, including
children, identification of new biomarkers, contemporary translation
of the immunobiology of tolerance in mice to humans, a better under-
standing of trafficking, the role of apoptosis in augmenting the
188 A.T. Borchers et al. / Autoimmunity Reviews 12 (2012) 174–194
immune response, the use of peptides and other therapeutic agents to
alter immune cell interactions and the role of innate immunity and
autoinflammation [4,5,34,40,177,348–367].
Take-home messages
• Lupus nephritis remains a major challenge and continues to be one
of the more severe manifestations of SLE.
• Although substantial research has helped define the pathogenetic
mechanisms of lupus nephritis, such research has not adequately
translated into new therapeutic agents.
• Early diagnosis and intervention are essential for favorable patient
outcomes.
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