PRIMER

Systemic lupus erythematosus

Arvind Kaul1, Caroline Gordon2, Mary K. Crow3, Zahi Touma4, Murray B. Urowitz4,
Ronald van Vollenhoven5, Guillermo Ruiz-Irastorza6 and Graham Hughes7
Abstract | Systemic lupus erythematosus (SLE) is an autoimmune disease that can affect many organs,
including the skin, joints, the central nervous system and the kidneys. Women of childbearing age
and certain racial groups are typically predisposed to developing the condition. Rare, inherited,
single-gene complement deficiencies are strongly associated with SLE, but the disease is inherited
in a polygenic manner in most patients. Genetic interactions with environmental factors, particularly
UV light exposure, Epstein–Barr virus infection and hormonal factors, might initiate the disease,
resulting in immune dysregulation at the level of cytokines, T cells, B cells and macrophages. Diagnosis
is primarily clinical and remains challenging because of the heterogeneity of SLE. Classification
criteria have aided clinical trials, but, despite this, only one drug (that is, belimumab) has been
approved for use in SLE in the past 60 years. The 10‑year mortality has improved and toxic adverse
effects of older medications such as cyclophosphamide and glucocorticoids have been partially offset
by newer drugs such as mycophenolate mofetil and glucocorticoid-sparing regimes. However, further
improvements have been hampered by the adverse effects of renal and neuropsychiatric involvement
and late diagnosis. Adding to this burden is the increased risk of premature cardiovascular disease in
SLE together with the risk of infection made worse by immunosuppressive therapy. Challenges remain
with treatment-resistant disease and symptoms such as fatigue. Newer therapies may bring hope of
better outcomes, and the refinement to stem cell and genetic techniques might offer a cure in
the future.

Correspondence to A.K.
Department of
Rheumatology, St. George’s,
University of London,
Cranmer Terrace,
London SW17 0RE, UK.
arvind.kaul@nhs.net
Article number: 16039
doi:10.1038/nrdp.2016.39
Published online 16 June 2016
Systemic lupus erythematosus (SLE) is a potentially fatal,
chronic, multisystem autoimmune disorder that typi-
cally affects women between puberty and menopause.
Defects can occur in many parts of the immune cascade
resulting in a striking heterogeneity of clinical presenta-
tions. Delay in diagnosis is associated with increased
damage to vital organ systems1.
Both genetic and environmental factors influence
the development of SLE. The concordance rate for SLE
in monozygotic twins is 25% but only 2% in dizygotic
twins, suggesting that genetic factors alone do not
explain the phenotype of SLE2. Some of the strongest
genetic links to SLE are the rare complement component
C1Q and C4 single-gene defects3,4. In most patients, SLE
is a quantitative trait with several genes contributing to
the risk of developing the disease; genome-wide associ-
ation studies implicate several candidate loci including
interferon (IFN) regulatory factor 5 (IRF5), mutations in
which are associated with increases in the levels of the
type 1 IFN family of molecules in patients with SLE, but
several additional loci are also important 5.
Candidate environmental risk factors include
UV light exposure, Epstein–Barr virus (EBV) infection,
endogenous retroviral sequences and multiple drugs.
The female preponderance in SLE suggests that endo-
crine factors are important. Indeed, when patients with
SLE are given oestrogen and progesterone hormone-­
replacement therapy, their risk of SLE flare is 1.34 times
that of women given placebo6. In addition, low levels
of dehydroepiandrosterone (DHEA), a steroid inter­
mediate in androgen and oestrogen formation, have
been associated with predisposition to SLE. However,
clinical trials using DHEA as a treatment showed less
effect than might be expected if DHEA deficiency was
the most important mechanism of the disease7.
The complexity of SLE is indicated by diverse clin­
ical features (including arthritis and neurological, renal,
cutaneous and gastrointestinal manifestations; FIG. 1)
and laboratory abnormalities (including haemato­
logical and serological changes, such as decreased levels
of complement and increased levels of autoantibodies).
Complicating the clinical picture are distinct disease
subsets including cutaneous lupus, which can be associ­
ated with negative serology, and drug-induced lupus,
which is associated with an array of medications and
antihistone antibodies. Comorbidities also add to the
complexity of the disease. In SLE cohorts, 29–46% of
patients have antiphospholipid antibodies depending

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 1

©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

Author addresses and prevalence varies even more widely from 19 to

1
Department of Rheumatology, St. George’s, University of
London, Cranmer Terrace, London SW17 0RE, UK.
2
Rheumatology Research Group, Institute of Inflammation
and Ageing, College of Medical and Dental Sciences,
University of Birmingham, Birmingham, UK.
3
Mary Kirkland Center for Lupus Research, Hospital for
Special Surgery, New York, New York, USA.
4
University of Toronto Lupus Clinic, Toronto Western
Hospital, Centre for Prognosis Studies in the Rheumatic
Diseases, Toronto, Ontario, Canada.
5
Unit for Clinical Therapy Research, Inflammatory Diseases
(ClinTRID), Karolinska Institutet, Stockholm, Sweden.
6
Autoimmune Diseases Research Unit, Department of
Internal Medicine, BioCruces Health Research Institute,
Hospital Universitario Cruces, University of the Basque
Country, Bizkaia, Spain.
7
The London Lupus Centre, London Bridge Hospital,
London, UK.
on ethnic origin and can be associated in ~15% of these
patients with the antiphospholipid syndrome, which
presents as recurrent pregnancy loss and/or arterial or
venous thrombosis8. In addition, patients with SLE are at
risk for accelerated cardiovascular disease (CVD), which
also contributes to damage accrual and mortality 9.
Mortality from SLE improved in the second half
of the twentieth century, with 10‑year survival at
60% in the 1950s to >90% in the 1980s. The improve-
ment in survival reached a plateau in the 1980s and
1990s despite improvements in diagnosis and treat-
ment. This may be owing to increasing levels of SLE-
associated damage accrual and morbidity that occur
with increasing lifespan10.
Measuring disease activity in routine clinical care
remains challenging because of disease heterogeneity.
Serological markers are in routine clinical use but do
not adequately predict flares or activity in all patients;
however, some clinical associations are important 11.
Global disease activity indices, such as the SLE Disease
Activity Index 2000 (SLEDAI‑2K), and organ-specific
scales, such as the British Isles Lupus Assessment Group
(BILAG) index, are used in clinical trials but are not
­routine bedside measures12.
This Primer explores the nature of SLE and its causes
and effects on patient well-being in more detail. In addi-
tion, the approaches to management and an outlook on
future directions are discussed.
Epidemiology
SLE is a global disease associated with an increased
risk of premature death. The number of people who
have SLE, the age of onset and the mortality risk varies
consider­ably between countries13. The best information
we have on the incidence, prevalence, mortality and
morbidity outcome are from Europe and North America;
less data are available from Africa, South America, Asia
and Australia (TABLE 1). Given that the disease is least
common in children (before puberty), many studies only
report data from adult populations14. Annual incidence
rates in the United States range from 2 to 7.6 per 100,000
159 per 100,000 depending on the defin­ition of SLE
used, methods of case ascertainment, age standard­
ization and the racial and ethnic background of the
population 15,16. Similarly, figures for Europe show
considerable vari­ation with annual incidence rates
between 1 and 4.9 per 100,000 and p ­ revalence ranging
from 28 to 97 per 100,000 (REFS 17,18).
SLE is more common in women than in men and
affects women particularly between puberty and meno­
pause14. The female/male ratio of 3/1 in children shifts
to about 9/1 between puberty and menopause, but is
up to 15/1 in some studies19,20. SLE is more common in
certain racial and ethnic groups15,20 (TABLE 1). People of
African origin, particularly those who have migrated to
North America or Europe, have a higher incidence and
prevalence of SLE than those of white north European
origin. These individuals also tend to develop the disease
at a younger age, have a higher risk of renal involvement
and of serious renal complications (end-stage renal dis-
ease)15,16,21. In a study in Georgia, USA, black women
had higher prevalence rates than white women (196.2
per 100,000 versus 59 per 100,000, respectively)15. There
is a high incidence of SLE in black people of African-
Caribbean origin20,22, Native Americans, (including
Alaska Natives) 23 and Indigenous Australians 24,25.
Although populations of people with Chinese back-
grounds have been reported to have an increased prev-
alence of SLE26, lower regional rates have been reported
from Korea27,28.
Mortality in patients with SLE has improved over
the past 30 years but remains considerably higher than
in people from the same geographical area without
SLE, with a standardized mortality ratio of 3 in a meta-­
analysis29. People of African, Chinese and Hispanic
origin with SLE have an increased frequency of SLE-
associated renal complications (that is, lupus n ­ ephritis)
— one of the strongest predictors of an increased
mortal­ity risk30,31. As a result, mortality risk due to active
SLE and associated renal disease is highest in patients
of these ethnicities and/or from low socioeconomic
backgrounds22,30,31. Other explanations for the variabil-
ity in mortality risk between different populations are
different beliefs and perceptions about the condition as
well as the availability of and adherence to treatments13.
Furthermore, infection constitutes another impor-
tant and common cause of death in patients with SLE
worldwide (a standardized mortality ratio of 5)29. CVD
is strongly associated with premature death later in the
disease course and in those who develop the disease at
an older age (>40 years)32.
Mechanisms/pathophysiology
SLE is caused by an autoimmune reaction in which
the innate and adaptive immune systems direct an
inappro­p riate immune response to nucleic acid-­
containing ­cellular particles. However, the production
of anti­bodies against these nucleic acids (antinuclear
antibodies (ANAs)) is fairly common in the general
popu­lation and not all people who have ANAs develop
SLE, suggesting that other mechanisms must promote

2 | 2016 | VOLUME 2 www.nature.com/nrdp

©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
 PRIMER

the progression of autoimmunity into overt disease. Genetic factors

Key determinants of this progression include genetic
susceptibility factors that shape immune function, sex
and stochastic factors that affect responses to exogen­
ous or endogenous triggers. A remaining mystery is
the significance of those autoantibody specificities
that characterize patients with SLE (BOX 1), particu-
larly those that are most specific to SLE compared with
other autoimmune disorders: anti-Smith (Sm) anti-
bodies, which are directed against a component of the
spliceosome, and anti-­double-stranded DNA (dsDNA)
antibodies. Experimental models of chronic virus infec-
tion, such as lymphocytic chorio­meningitis virus and
human immuno­deficiency virus, suggest a framework
for understanding some aspects of the immunopatho­
genetics of SLE, particularly with regards to the sus-
tained production of type I IFNs seen in many patients
with the disease33 (BOX 2).
Neurological complications (50%)
Constitutional symptoms Cutaneous and mucosal
and fevers (70%) complications (70%)
Pleural effusion
(40%)
Pericarditis
and effusion
(20%)
Renal
complications
(30%)
Gastrointestinal
complications (50%)
Haematological
complications
(50%)
Arthritis and
musculoskeletal
complications
Raynaud (85%)
phenomenon
(20%)
Figure 1 | Clinical heterogeneity of SLE. The multifaceted nature of systemic lupus
Nature Reviews | Disease Primers
erythematosus (SLE) is shown by the number of different organ systems that can be
affected. In addition, each organ-specific complication can manifest in different ways.
For example, cardiac complications can be the consequence of myocarditis, pericarditis,
pericardial effusion, pulmonary hypertension and Libman–Sacks endocarditis.
Gastrointestinal involvement varies from oral ulcers to full-blown lupus enteritis,
pancreatitis, hepatitis and ascites. Neurological involvement is complex with symptoms
such as headache, seizures and thrombotic features including stroke. The average
frequency of the most common complications is indicated in parentheses.
Low-frequency single-gene mutations with substantial
impact on SLE susceptibility have been described34.
In addition, >100 genetic loci associated with SLE have
been detected, most with a small effect on risk. When
sufficient genetic risks aggregate in an individual, they
may achieve a threshold for susceptibility to SLE. Many
variants represent regulatory elements rather than
­coding sequences, and a common theme is that they
encode proteins implicated in important molecular
pathways that alter immune function, including the
generation of self-antigens and the activation of innate
and adaptive immune responses (BOX 3).
The rare but high-risk mutations include those
that produce deficiencies in complement pathway
gene products (including C2, C4 and C1q), which
might contribute to SLE pathogenesis by impairing
the clearance of cellular debris34, with increased avail-
ability of nucleic acid-containing cell products as a
consequence35. The ancestral major histocompatibil­
ity complex (MHC) 8.1 haplotype associated with
SLE susceptibil­ity covers the majority of the MHC
loci including the HLA‑B8 and HLA‑DR3 alleles and
a short segment of C4B, but not C4A. The MHC 8.1
haplotype influences early stages of immune activation
by determining whether anti-dsDNA autoantibodies,
anti­b odies specific for RNA-associated proteins or
other types of autoantibodies are produced through
T cell-dependent B cell differentiation, possibly as a
result of MHC restriction36. The relative risk related
to the C4A‑null allele is twice that of either HLA‑B8
or HLA‑DR3, indicating the importance of C4 for
disease susceptibil­ity 37. In addition to its role in clear-
ance of apoptotic cell debris, C1q might provide pro-
tection from SLE by directing stimulatory immune
complexes to monocytes rather than IFNα‑producing
­plasmacytoid dendritic cells38.
Mutations in genes encoding nucleases (for ­example,
TREX1) that cleave either DNA or RNA have been
found in SLE and in a SLE-like disease — Aicardi–
Goutières syndrome, which is characterized by skin
lesions, autoantibodies, central nervous system dis-
ease and high levels of type I IFNs39. These mutations
and genetic associations support a role for stimulatory
cytoplasmic nucleic acids as triggers for immune system
activation in SLE40.
A large number of SLE-associated single-nucleotide
polymorphisms are found in genes that encode proteins
involved in the induction of or response to type I IFNs.
Genetic variants of IRF5 and IRF7, which are involved
in signalling through endosomal Toll-like receptors
(TLRs) activated by DNA or RNA, are examples of
variants that can be mapped to molecular pathways
­responsible for innate immune activation41.
Another set of SLE-associated gene variants contrib-
utes to altered thresholds for lymphocyte activation or
efficiency of immune cell signalling. In addition to the
MHC 8.1 haplotype that is important in determining
whether anti-DNA autoantibodies, antibodies specific
for RNA-associated proteins or both types of auto­
antibodies are produced, possibly as a result of MHC

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 3

©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

restriction36, these SLE-associated variants encode for Environmental triggers

proteins involved in cytokine signalling (for ­example,
signal transducer and activator of transcrip­t ion  4
(STAT4)) and in the efficiency of signalling down-
stream of T  cell and B  cell surface antigen recep-
tors (for  ­e xample, tyrosine-protein phosphatase
non-­receptor type 22 (PTPN22), tyrosine-protein kin­
ase LYN, B cell ­scaffold protein with ankyrin repeats
(BANK), B lymphocyte tyrosine kinase (BLK) and
tumour necrosis factor-­α-induced protein 3 (TNFAIP3))
(REF. 42) (BOX 3). SLE-associated variants in kallikrein-­
encoding genes are associated with protection from or
vulnerability to renal damage, and overexpression of
Klk1 in the ­kidneys of a mouse model of SLE reduced
inflammation and o ­ xidative damage43.
Female predominance
Among the characteristic features of SLE, the extreme
sex skewing remains poorly understood. Hormonal
contributions to immune system activation represent a
component of the female predominance of the disease.
Oestrogen can modulate the activation of lympho­
cytes, and prolactin is expressed at increased levels in
serum of patients with SLE compared with controls,
but the specific mechanisms by which prolactin might
alter immune function in SLE are not clear. In addition
to a contribution of hormones to increased immune
activation, additional concepts should be entertained
to understand the female predominance in SLE. The
prevalence of Klinefelter syndrome, which is character­
ized by a 47XXY genotype, is increased 14‑fold among
men with SLE compared with men without SLE, sug-
gesting that an X chromosome gene-dose effect is an
important contributor to SLE susceptibility 44. The
carefully orchestrated genomic events in germ cells
and associated somatic cells in the ovaries, with periods
of genome hypomethylation, might provide a source of
stimulatory nucleic acid-containing complexes that
could access TLR-dependent or TLR-independent
pathways and result in immune activation45.
Clinical manifestations that are present at the time
of diagnosis, including fatigue and arthralgias (joint
pain), have led to the suggestion that a viral infection
— especially with EBV — might trigger the disease.
The T cell response to EBV infection can be defec-
tive in patients with SLE, which might contribute to
the increased numbers of EBV-infected mononuclear
cells and increased copy number of EBV DNA in the
blood of patients with SLE46. EBV might contribute to
innate immune system activation and B cell differenti­
ation, and could stimulate the production of auto­
antibodies that are specific for amino acid sequences
shared by self-proteins and EBV-encoded proteins.
EBV-encoded small RNAs induce immune activation
through the expression of type I IFNs after binding
to dsRNA-dependent protein kinase and activating
a TLR-independent pathway. In addition, antibodies
specific for the viral Epstein–Barr nuclear antigen 1
(EBNA1) protein can crossreact with dsDNA, suggest-
ing that EBV infection could induce an auto­immune
response47. The molecular basis of this apparent cross-
reactivity is not fully understood, but might be based
on common conformational epitopes between DNA
and EBNA1.
Two well-described triggers of SLE — UV light
and certain drugs (TABLE 2) — are likely to promote
the pathogenesis of SLE through their effects on DNA.
UV light can induce DNA breaks that might alter
gene expression, generate nucleic acid fragments or
lead to apoptotic or necrotic cell death. Altered DNA
methylation has been proposed as a likely mech­anism
of drug-induced SLE 48. For example, hydralazine
inhibits extracellular signal-regulated kinase pathway
signalling, which results in decreased expression of
DNA methyltransferase 1 (DNMT1) and DNMT3A,
enzymes that mediate DNA methylation49. Altered DNA
methylation modifies gene expression and might also
expose potential ligands for TLR-mediated immune
system activation.

Table 1 | Incidence and prevalence of SLE in selected countries

Country or population Incidence (per 100,000) Prevalence (per 100,000)
Total Women Men Total Women Men Black White
people people
United States (Georgia)15 5.6 9.2 1.8 73 128 15 119 33
United States (Michigan)16 5.5 9.3 1.5 73 129 13 112 48
Barbados 22
NA 12.2* 0.8* NA 153* 10* NA NA
Denmark17 1 NA NA 28 NA NA NA NA
United Kingdom20 4.6 7.8 1.3 88 152 22 525* 124
American Indian Health Service23 7.4 10.4 NA 178 271 54 NA NA
Taiwan 26
4.9 ‡
NA NA 98‡
NA NA NA NA
Korea27,28 NA NA NA 19–22‡ NA NA NA NA
2.5‡ NA NA 27‡ NA NA NA NA
Australia24,25 NA NA NA NA NA NA 74§ 19
NA NA NA 45 NA NA 93 NA
NA, not available; SLE, systemic lupus erythematosus. *The majority of the study population are black people of African-Caribbean
origin. ‡Chinese origin. §Indigenous Australians.

4 | 2016 | VOLUME 2 www.nature.com/nrdp

©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
 PRIMER

Box 1 | Autoantibodies in SLE

Autoantibody specificities overlap between the different clinical manifestations of
systemic lupus erythematosus (SLE), and positivity for a specific antibody does not
necessary mean that a certain organ will be affected. Although complement
C1q‑specific antibodies are linked to renal manifestation of SLE, these antibodies can
be detected in patients with inactive SLE without renal manifestations. In addition,
the levels of double-stranded DNA (dsDNA)-specific autoantibodies can be raised in
quiescent SLE, although a rising trend usually indicates a flare in SLE. Targets of
autoantibodies associated with disease manifestations of SLE are listed below.
• Neuropsychiatric SLE: ribosomal‑P proteins (phosphorylated proteins of the ribosome
complex) and neuronal antigens
• Lupus nephritis: C1q, dsDNA and Smith (Sm)
• Subacute cutaneous lupus and secondary Sjögren syndrome: Ro
(Sjögren syndrome-related antigen A (SSA)) and La (SSB)
• Interstitial lung disease and shrinking lung syndrome: U1 ribonucleoprotein (U1‑RNP)
and Ro (SSA)
• Lupus arthritis: Sm
• Autoimmune haemeolytic anaemia: red blood cells
• Thrombocytopaenia: platelets
• Leukocytopaenia: dsDNA
• Antiphospholipid syndrome: prothrombin and β2‑glycoprotein 1
• Congenital fetal heart block and neonatal lupus: Ro (SSA)
Tobacco smoking is also a risk factor for SLE, with a
dose–response association between the number of cig-
arettes smoked per year and the development of SLE50.
Smoking might provide an inflammatory stimulus to
epithelial or mononuclear cells in the lungs, promot-
ing protein modification or nonspecific inflammation.
Silica, often encountered by those working in mining
or construction occupations, has also been proposed
as a potential pathogenetic factor in SLE on the basis
of its known capacity to function as an adjuvant for
­heightening immune responses51.
Innate immune system activation
Products of apoptotic cells and/or impaired clearance
of apoptotic cells focus the adaptive immune response
on nucleic acids and their associated proteins but also
act as potential direct triggers of innate immune sys-
tem activation (FIG. 2). Nucleic acid-containing immune
complexes and cytoplasmic RNA and DNA, including
nucleic acids enriched in endogenous retrotransposon
sequences, are potential stimuli for the activation of
nucleic acid-responsive endosomal TLRs and TLR-
independent nucleic acid sensors, leading to type I
IFN production and immune dysfunction in SLE33,52.
This observation complements the demonstration of
the expression of multiple type I IFN-inducible genes
in peripheral blood cells and affected tissue of patients
with SLE, referred to as the ‘IFN signature’ (REFS 53–55).
TLRs present in endosomes in immune cells, particu-
larly TLR7 (its ligand is single-stranded RNA) and
TLR9 (its ligand is unmethylated CpG-rich DNA), are
activated by immune complexes that are internalized
into the cytoplasm through Fc receptor–Fc fragment
interactions56. Moreover, autoantibodies with specifi­
city for RNA-binding proteins (such as Ro, La, Sm
and RNP) are strongly associated with high expression
levels of IFN-induced genes in peripheral blood cells
of patients with SLE57. In addition, data from mouse
models of SLE link activation of the TLR pathway with
the production of particular autoantibodies. Finally,
activation of TLR7 in particular is associated with the
production of anti‑Sm antibodies58. These observations
point to an important role of RNA-containing immune
complexes and TLR7 in innate immune activation, IFN
production and SLE development 57,59. However, recent
data suggest that the TLR-independent pathway of
innate immune system activation driven by cyto­plasmic
nucleic acids and their sensors, including retinoic
acid-inducible gene 1 (RIG‑I; also known as DDX58),
melanoma differentiation-associated protein 5 (MDA5;
also known as IFIH1) and cyclic GMP–AMP synthase
(cGAS), may also contribute to SLE ­p athogenesis,
­perhaps in other cells such as epithelial cells60,61.
Although plasmacytoid dendritic cells are the main
source of type I IFNs, other cell types might be involved
in amplifying IFN signalling. Microarray  analy­
ses showed that an IFN gene expression signature in
peripheral blood cells was associated with the expres-
sion of genes that are typically expressed in granulocytes
and neutrophil extracellular traps (NETs), suggesting a
potential role of these factors in innate immune system
activation53. NETS comprise a network of extracellular
fibres that contain DNA and pro-inflammatory pro-
teins extruded by neutrophils. NETs might facilitate
the trafficking of DNA-containing immune complexes
to the TLR-containing intracellular endosome, induce
the production of type I IFNs by plasmacytoid den-
dritic cells, serve as a source of relevant self-antigens
for presentation to T lymphocytes and mediate vascular
­damage and thrombosis62.
Adaptive immune system activation
T cells. T cells are important contributors to SLE patho-
genesis. Deficiencies or alterations in T cell signalling,
in the production of cytokines, in proliferation and in
regulatory functions have been documented in patients
with SLE63. Although in vitro experiments support the
capacity of IL‑21, B cell-activating factor (BAFF, also
known as BLyS or TNRSF13B) and TLR ligands to
mediate antibody production by B cells, CD4+ T cells
are recognized as the most efficient drivers of B cell
differentiation64. T cells derived from patients with
SLE readily express CD40 ligand (CD40L) after activ­
ation and maintain the expression of this important co‑­
stimulatory molecule longer than T cells derived from
healthy controls65, leading to augmented help for the
activation and differentiation of B cells. The molecu­
lar basis of the altered T cell activation in patients
with SLE is complex. Altered expression of compo-
nents of Fc receptor signalling might have a role, for
example, substitution of the T cell receptor-ζ (TCRζ)
chain with the common-γ chain (TCRγ)66. Augmented
intra­cellular calcium signalling and hyperpolarization
of mitochondria have been observed in the presence of
TCRγ compared with TCRζ, which can sensitize T cells
for necrosis67. Correction of this defect can normalize
T cell signalling 66.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 5

©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

Box 2 | Chronic viral infection as a model for SLE pathogenesis
Recent data have characterized a distinction between effective immune responses in
the setting of some viral infections (for example, lymphocytic chorimeningitis virus
(LCMV), Armstrong strain or simian immunodeficiency virus infection in African green
monkeys) and a chronic and damaging immune response to infection with other viruses
(for example, LCMV clone 13 or human immunodeficiency virus type 1 (HIV‑1)). Chronic
and damaging immune responses to infection are associated with sustained production
of type I interferons (IFNs), a sustained signature of increased expression of type I
IFN-induced gene transcripts, altered T cell function and chronic tissue inflammation
and damage. The immune alterations observed in systemic lupus erythematosus (SLE)
show a clear resemblance with the chronic immune response associated with
well-described models of virus infections. Among the immune alterations observed in
patients with SLE that are also characteristic of chronic virus infection are a sustained
expression of type I IFNs; increased and sustained production of pro-inflammatory
mediators, such as IL‑6, IL‑10 and tumour necrosis factor (TNF); altered expression of
some cell surface receptors, including programmed death ligand 1 (PDL1) and
TNF-related apoptosis-inducing ligand (TRAIL; also known as TNFSF10); and a shift in
T cell differentiation towards a T follicular helper cell phenotype. The consequences of
these altered immune functions include sustained and poorly regulated macrophage
activation; impaired T cell function and regulation of cell death; excessive B cell
differentiation; the production of autoantibodies and immune complexes; and
widespread tissue and organ inflammation and damage.
T cells derived from patients with SLE studied ex vivo
show hypomethylation of CG‑rich DNA sequences and
promoters of IFN-regulated genes68. Epigenetic modifi­
cations might thus contribute to the SLE phenotype, as
DNA demethylation of mouse and human T cells results
in T cell-proliferative responses to usually subthreshold
interactions with autologous macrophages. Increased
expression of lymphocyte function-associated anti-
gen 1 (LFA1) is the most likely factor responsible for
the produc­tive interactions between macrophages and
T cells that result in increased T cell proliferation.
Generalized lymphocytopaenia is a typical
character­istic of SLE, but the expansion of specific
T cell populations has been described. The population
of T follicular helper cells, which promote differenti­
ation of autoantibody-producing B cells, is expanded
in SLE69. As T follicular helper cells may be essential
for the differ­entiation of pathogenetic autoantibody-­
producing B cells, they represent an important thera-
peutic target. The expansion of a population of CD8+
cells with a memory phenotype is associated with
poor prognosis of SLE, possibly owing to their role in
mediating tissue damage70. Regulatory T (Treg) cells,
with the capacity to suppress immune responses, and
T helper 17 (TH17) cells, which promote inflammation
by the production of IL‑17, have been intensively stud-
ied in recent years. Some studies have shown a relative
depletion in the number of Treg cells, increased numbers
of TH17 cells and increased levels of IL‑17 in SLE71. The
functional consequences of these alterations in human
SLE are still not clear. Decreased production of IL‑2 is
a character­istic feature of T cells derived from patients
with SLE and of the T cells of individuals without SLE
who also carry the MHC 8.1 haplotype37. Although IL‑2
deficiency was initially linked to the poor proliferative
responses of SLE T cells stimulated with autologous
T cells, allogeneic T cells or soluble antigen, the recog­
nition that IL‑2 is important for the maintenance of
Treg cells suggests another mechanism through which
impaired production of IL‑2 might contribute to
immune system a­ ctivation and autoimmunity 72.
B cells. B cell regulation is also impaired in SLE, contrib-
uting to the production of autoantibodies, cytokines and
augmented presentation of antigen to T cells. Increased
availability of T cell help for B cell differentiation as
well as B cell survival, proliferation and differenti­ation
factors (including BAFF and IL‑21) and activation
of TLRs all contribute to autoimmunity, but intrinsic
differences in threshold for the activation and signal-
ling of B cells in mouse lupus models have also been
described73. SLE-associated genetic variants encoding
several kinases, phosphatases and adaptor molecules,
such as BLK, BANK and PTPN22, contribute to altered
counter-selection of self-reactive B cells or antigen-­
mediated B cell activation42. SLE memory B cells show
modest decreases in the expression of the inhibitory
Fc receptor FCGR2B, and mouse B cells studied in an
in vitro system demonstrate altered cytokine produc-
tion when engaged by nucleic acid-containing immune
complexes74,75. Long-lived plasma cells are maintained
by chemokines and stromal cell products in protec-
tive bone marrow niches and are proposed sources of
anti‑Sm and anti‑Ro autoantibodies that are refractory
to modulation by immunosuppressive or B cell depletion
therapy 76. By contrast, circulating plasmablasts (plasma
cell progenitors) are sources of anti-dsDNA antibodies,
the levels of which fluctuate in some patients in associ­
ation with variations in disease activity and might be
more amenable to anti-B cell therapy 77.
Autoimmunity in SLE
Autoantibodies are traditionally viewed as essential
mediators of pathology in SLE, particularly when they
form immune complexes. Virtually all patients with SLE
are positive for ANAs or other characteristic SLE auto­
antibodies (BOX 1). Autoantibodies in SLE can be categor­
ized in relation to their targets: DNA and DNA-binding
proteins, which are typically aggregated with histones in
nucleosomes; RNA and RNA-associated proteins, which
are aggregated in cytoplasmic or nuclear ribonucleo­
protein particles; β2‑glycoprotein 1 in association with
phospholipids; and cell membrane proteins, typically
those expressed on blood cells. Among those, anti-
dsDNA and anti‑Sm are most specific for SLE. Anti‑C1q
antibodies, which recognize neo-epitopes of C1q bound
to early apoptotic cells, are associated with SLE activity
and with proliferative lupus nephritis and are thought to
be pathogenetic78.
The pathogenetic antibodies in SLE undergo
immuno­globulin class switching driven by CD4+ T helper
cells or TLR ligands together with IL‑21 or BAFF. A shift
from a predominant polyclonal IgM profile towards
IgG occurs over time in most patients with SLE and
with disease progression and development of tissue
­damage. Class-switched IgG antibodies are better able
to access extravascular spaces than IgM antibodies.
Some IgM antibodies that have self-reactivity are viewed
as protective, with the switch from IgM to IgG or IgA

6 | 2016 | VOLUME 2 www.nature.com/nrdp

©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
 PRIMER

representing an important point of altered immune
regu­lation that contributes to SLE immunopathogenesis.
Some IgM natural antibodies react with apoptotic cells
and inhibit their activation through TLRs79,80. Arginines
in the complementarity-determining region 3 region of
anti-dsDNA antibodies are characteristic of SLE auto­
antibodies and influence binding to their DNA t­ arget.
Some antibodies unexpectedly bind to two distinct
self-antigens. For example, some anti-dsDNA anti­bodies
also bind to a peptide that is a feature of ­glutamate
­receptors on central nervous system neurons81.
The role of SLE autoantibodies in the patho­genesis
of the disease has traditionally focused on deposition of
immune complexes in the skin, the renal glomeruli
and other sites of tissue injury, along with a potential
contrib­ution of direct targeting of antibodies to antigens
­deposited in situ82. In recent years, with the recognition
that nucleic acid-containing immune complexes can
directly induce cell signalling and new gene transcrip­tion
after accessing endosomal TLRs59, an additional patho-
genetic role for autoantibodies as immune m ­ odulators
has been defined.
Mechanisms of target organ damage
Clinical disease is ultimately a reflection of tissue dam-
age mediated by the inflammatory consequences of
autoimmunity and immune system activation, along
with an exaggerated or aberrant repair response.
A trad­itional view of pathogenetic mechanisms of lupus
nephritis involves activation of the complement system
by immune complexes deposited in the glomerulus,
recruitment of myeloid cells (particularly neutrophils)
and the release of enzymes from neutrophil granules and
reactive oxygen intermediates from macrophages83.
However, deposition of autoantibodies or immune
complexes in a target organ is not sufficient for the
gener­ation of tissue damage. Mouse models of SLE
that are deficient in components of the complement
system or Fc receptors have been used to demonstrate
a requirement for immune effector mechanisms in
Box 3 | Pathogenetic roles of SLE-associated genetic variants
Availability of self-antigens
• Impaired nucleic acid degradation: TREX1, DNASE1, DNASE1L3 and RNASEH2
• Increased cell death: ATG5 and MSH5
• Impaired cell debris clearance: FCGR2A, FCGR2B, FCGR3A, FCGR3B, C1Q, C2 and
C4A or C4B
Activation of the innate immune system
• Increased type I interferon production: IRF5, IRF7, IFIH1, TREX1, RNASEH2, TNFAIP3,
SLC15A4, RASGRP3 and FCGR2B
• Increased response to type I interferon: STAT4, TYK2 and IRF8
• Altered antigen presentation: HLA‑DR2 and HLA‑DR3
Dysfunction of the adaptive immune system
• Altered lymphocyte signalling: PTPN22, BLK, LYN and BANK1
• Altered lymphocyte differentiation: PRDM1, ETS1, IKZF1 and TNFSF4
• Increased levels of lymphocyte factors: IL10 and IL21
SLE, systemic lupus erythematosus.
addition to local deposition of autoantibodies. NETs
might be important in initiating or amplifying tissue
pathology 84,85. Studies of renal infiltrating cells at vari-
ous disease stages have identified a monocyte population
that has undergone differentiation to mediate what is
apparently uncontrolled tissue repair, contributing to
sclerosis and organ dysfunction86. Although pathological
examination of lupus nephritis traditionally focused on
the glomerulus, T lymphocytes and B lymphocytes that
infiltrate the renal interstitium may at least be as impor-
tant for organ damage as those in the glomerulus. The
presence of B cells in the interstitium is associated with
increased risk of future renal failure87, and the particular
T cell subsets that infiltrate the kidney may be important
in mediating or controlling tissue damage.
Data from mouse models indicate that the inter­
actions between myeloid cells and T cells that result in
T cell activation, proliferation and the production of
cytokines may differ from one organ to another. It is
apparent that elucidation of the microenvironment that
characterizes each tissue and organ targeted for damage
in SLE will be important for understanding the relative
contributions of immune cells and their products in each
of those tissues88.
Among the products of the immune system that
promote inflammation and contribute to a local tissue
environment that is supportive of tissue damage are the
cytokines generated by both innate and adaptive immune
system cells. In addition to type I IFNs, signalling path-
ways activated by cytokines, including IFNγ, IL‑6, IL‑12,
IL‑21 and IL‑23, mediate inflammation by altering the
function of local tissue cells, including endothelial and
stromal cells, and activating patho­genetic T cells, B cells,
macrophages and dendritic cells in target organs. These
cells collect in lymphoid aggregates and collaborate to
amplify the production of autoantibodies and effec-
tor T cells, leading to the SLE phenotype. One of the
more important signalling pathways is the Janus kinase
(JAK)–STAT system. The importance of this signalling
pathway in immune regulation and inflammation has
been exploited with the development of small-molecule
JAK inhibitors that are approved for the treatment of
rheumatoid arthritis and are currently being studied in
patients with SLE.
In addition to mechanisms that involve the immune
system, target organs themselves are recognized to
contrib­ute to SLE pathology. Altered structure and func-
tion of venous and arterial blood vessels, seen as peri­
articular (concentric ‘onion-skinning’) in the spleen, and
microangiopathy and associated microthrombi in the
kidneys and endothelial dysfunction have been associ­
ated with premature atherosclerosis in SLE89. Recent
studies have focused on the effect of type I IFNs on
endothelial cells and endothelial cell progenitor cells and
have postulated that increased levels of IFNs contribute
to impaired endothelial repair after vascular damage89.
NETs and pro-inflammatory high-density lipoproteins,
which are increased in patients with SLE with carotid
plaque, may also disrupt the vasculature or promote
premature atherosclerosis90. These mechanisms are in
addition to the previously described role of complement

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 7

©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

Table 2 | Selected drugs implicated in drug-induced SLE cardiac comorbid­ities, such as pleural or pericardial
pathology, joint deformities or skin rash, among others95.
Drug Indication Prevalence Prevalence In clinical practice, health care providers tend to use
of ANAs of clinical
(%) manifestations (%) the revised American College of Rheumatology (ACR)
classifi­cation criteria for SLE96,97 (BOX 4)  for diagnosis,
Procainamide Anti-arrhythmic agent 75 15–20 although these criteria were originally developed to
Minocycline Broad-spectrum antibiotic 90 10–15 ­classify and not to diagnose SLE. The main purpose
Hydralazine Vasodilator 15–45 5–10 of classification criteria is to enhance the ability to iden-
tify, in a standardized manner, a well-defined group of
Isoniazid Antibiotic 20 <1
patients. In general, classification criteria are applied in
Methyldopa Psychoactive drug 19 <2 clinical ­trials and in research settings to select a homo­
Chlorpromazine Antipsychotic 20–50 <1 genous group of patients97,98. Classification criteria
Sulfasalazine Rheumatoid arthritis 10 <1 require a very high specificity and preferably a high
sensitivity. Conversely, diagnostic criteria require both a
Carbamazepine Epilepsy and neuropathic pain 1–25 <1
high specificity and a high sensitivity, which is very dif-
IFNα Hepatitis B and hepatitis C 11–53 <1 ficult to achieve99. The diagnosis of SLE is very challeng-
Anti-TNF Rheumatoid arthritis 18–72 0.1–2.1 ing because there are no generally accepted diagnostic
biologics and seronegative ­criteria. Recognizing the difficulty in developing diagnos-
spondyloarthropathies tic criteria for rheumatic diseases, the ACR Classification
Use of the specified drugs for >1 month might result in fever, musculoskeletal involvement and and Response Criteria Subcommittee of the Committee
serositis but usually without renal or neuropsychiatric involvement. Drug-induced systemic lupus
erythematosus (SLE) is usually milder than idiopathic SLE. Serological abnormalities include on Quality decided not to consider funding or endorsing
homogenous antinuclear antibodies (ANAs) with antihistone antibodies. Withdrawal of the drug diagnostic criteria.
generally leads to resolution of symptoms. IFNα, interferon-α; TNF, tumour necrosis factor. It is important to note that the ACR classifica-
tion c­ riteria for SLE do not capture the entire range
activation products C3a and C5a and increased expres- of manifest­ations that can be encountered in patients
sion of the endothelial cell surface adhesion molecules with SLE but focus on the more-prevalent manifesta-
E‑selectin, vascular cell adhesion molecule 1 (VCAM1) tions. For instance, the mucocutaneous manifestation
and intercellular adhesion m ­ olecule 1 (ICAM1) in the in the ACR classification criteria is focused on malar
endothelium of patients with lupus flares91. In addition, rash (FIG. 3), photosensitivity, discoid lupus and oral ulcers
mesangial cells in the kidney can function as antigen-­ (BOX 4). Other skin manifestations, such as subacute cuta-
presenting cells and keratinocytes in the skin can gener- neous lupus (annular (ring-shaped) and psoriasiform
ate self-antigenic material when undergoing UV‑induced (flaking)) and other forms of chronic cutaneous lupus
apoptosis, in both cases contributing to the development (lupus panniculitis or profundus and lupus erythema-
of autoimmunity and SLE92,93. The renal podocyte is tosus tumidus), are not represented and therefore do
partly responsible for proteinuria in lupus nephritis, and not count towards the classification criteria, which is a
abnormal expression of molecules or activity in processes drawback for the use of these criteria in a diagnostic set-
that protect against (for example, the kallikreins) or pro- ting. Another example is the neurological system, which
mote podocyte injury or apoptosis have been described is very poorly represented in the ACR classification
in SLE94 and might serve as new therapeutic targets. ­criteria and includes only two syndromes (seizures and
psychosis) and lacks other important syndromes, such
Diagnosis, prevention and screening as organic brain syndrome, cranial nerve involvement,
Diagnosis versus classification SLE-associated headache and cerebrovascular accident,
SLE is a heterogeneous autoimmune disorder with a among others100. Despite these disadvantages of the ACR
great variability in clinical manifestations and disease classification criteria to diagnosis SLE, they have served
severity, which can vary from mild to moderate and a practical function when applied to recruiting patients
severe. For example, skin inflammation might be limited with SLE for clinical trials and cohort studies.
to the scalp in one patient, whereas the associated skin In general, the ACR classification criteria for SLE have
rash might involve the scalp, trunk and upper extremity more practical value for patients with advanced disease.
in another patient. These issues must all be considered This can be explained by the fact that the ACR classifica-
when recruiting patients for clinical trials. Failure to tion criteria require the presence of four or more items to
consider these issues in developing inclusion criteria for meet the definition of SLE. However, it is not unusual for
trials may have been one of the reasons for failure of patients with SLE to have fewer than four criteria present
recent clinical studies in SLE. at the onset of the disease. Patients with SLE continue to
The diagnosis of SLE is made based on clinical accrue SLE-specific clinical findings and autoantibodies
manifest­ations and laboratory tests, including the over time97,101.
detection of autoantibodies, functional tests and imag- The current ACR classification criteria have a sensitiv-
ing. The majority of SLE manifestations are defined by ity of 86% and a specificity of 93%. The Systemic Lupus
the presence of both subjective and objective findings. International Collaborating Clinics (SLICC) recognized
Subjective findings include chest pains, arthralgias and the disadvantages of the ACR classification criteria lack-
headaches, whereas objective findings include electro- ing many cutaneous and neuropsychiatric manifesta-
cardiographic or echocardiographic confirmation of tions and serum complement levels and proposed the

8 | 2016 | VOLUME 2 www.nature.com/nrdp

©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
 PRIMER

Triggers
Genetic, environmental, hormonal and viral factors

Defective apoptosis Immune system dysregulation

Modified nucleosomal material T cell, B cell and cytokine defects

Innate immune response Adaptive immune response

Immune
complex Apoptotic
cell
MHC TCR

TLR Antigen
T cell Enhanced
DC immune
Nucleic T cell
PDC acid response
Endosome
Failure of
anergy
Type I IFNs CD40L
Fc receptor NET Cytokines

Antibody

Macrophage PMN CD40

Nucleic acid
sensor B cell TLR
Class switching
Increased
autoantibody
Non-haematopoietic cell production

Autoantibody production
Complement activation
Tissue damage

Figure 2 | Immune dysfunction in SLE. Several environmental factors can trigger disease onsetReviews
Nature and they can be Primers
| Disease
potentiated by polygenic or monogenic traits, which confer an increased risk of disease. Triggers of innate immune system
activation might include nucleic acids that activate cytoplasmic sensors or microbial infection, or apoptotic or necrotic
cell debris. These triggers can interact with Toll-like receptors (TLRs) on plasmacytoid dendritic cells (PDCs). In addition,
aberrant cytoplasmic nucleic acid-sensing mechanisms in other cells, possibly epithelial cells, may enable direct
stimulation of type I interferon (IFN) release, allowing immune stimulation, and neutrophil extracellular traps (NETs) might
also have a role. Type I IFNs are central to the activation of the innate immune system in many patients. Interaction of type I
IFNs with their receptors induces signalling through the Janus kinase (JAK)–signal transducer activator of transcription
(STAT) pathway and transcription of hundreds of IFN-responsive genes — the ‘interferon signature’ — encoding proteins
that are involved in immune function regulation. Activation of antigen-presenting dendritic cells (DCs) by type I IFNs
promotes their capacity to effectively present antigens (including self-antigens) to T cells. The generation of T effector
cells results in the production of cytokines and the expression of cell surface molecules that support amplification of a
self-directed immune response as well as inflammation. With a steady supply of apoptotic material bound to factors
(including nucleosomes), B cells are driven to produce autoantibodies facilitated by CD40 (also known as TNR5)–CD40
ligand (CD40L) interactions. T cell interactions are important in driving B cell differentiation and autoantibody production,
as are B lymphocyte stimulator, TLR ligands and tumour necrosis factor (TNF) secreted by DCs. Normal anergic responses
(that is, processes that suppress an immune response against self-antigens) are lost, leading to failure to delete
self-reactive clones of T cells and B cells. The generation of immune complexes — containing nucleic acids, nucleic
acid-binding proteins and autoantibodies directed against those components — sets the stage for inflammation and
organ damage. Perpetuation of damage occurs when the immune complexes are deposited in target tissue with
amplification of immune system activation after accessing endosomal TLRs and triggering downstream signals that
induce IFNα and other pro-inflammatory mediators. MHC, major histocompatibility complex; SLE, systemic lupus
erythematosus; TCR, T cell receptor.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 9

©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

Box 4 | 1997 update of the 1982 ACR revised criteria for classification of SLE
Although in clinical trials, four or more parameters are required to classify SLE, many
patients — especially in early disease stages — have fewer parameters. In addition,
the complete range of systemic lupus erythematosus (SLE) phenotypes is not taken
into account, which limits the use of these classification criteria for diagnostic
purposes in routine clinical care.
Malar rash
• Fixed, flat or raised erythema (superficial reddening of the skin) over the malar
eminences, but tends to spare the nasolabial folds
Discoid rash
• Erythematous raised patches with adherent keratotic scaling and follicular
plugging
• Atrophic scarring may occur in older lesions
Photosensitivity
• Skin rash as a result of unusual reaction to sunlight
• Diagnosis is based on patient history or physician observation
Oral ulcers
• Oral or nasopharyngeal ulceration, usually painless and based on physician
examination
Non-erosive arthritis
• Tenderness, swelling or effusion in two or more peripheral joints
Pleuritis or pericarditis
• Pleuritis is defined by a convincing history of pleuritic pain, rubbing heard by
a physician or evidence of pleural effusion
• Pericarditis is documented by an electrocardiogram, rubbing heard by a physician
or evidence of pericardial effusion
Renal disorder*
• Persistent proteinuria of >0.5 g daily or >3 on urine dipstick if quantification
is not performed
• Cellular casts in urine, including red blood cells or haemoglobin, and can be
granular, tubular or mixed
Neurological disorder
• Seizures or psychosis in the absence of offending drugs or known metabolic
derangements, such as uraemia, ketoacidosis or electrolyte imbalance
Haematological disorder*
• Haemolytic anaemia with reticulocytosis
• Leukocytopaenia: <4,000 per mm3 on two or more occasions
• Lymphocytopaenia: <1,500 per mm3 on two or more occasions
• Thrombocytopaenia: <100,000 per mm3 in the absence of causative drugs
Immunological disorders*
• Anti-DNA autoantibody
• Anti‑Sm autoantibody
• Antiphospholipid autoantibodies (including an abnormal serum level of IgG or IgM
anticardiolipin autoantibodies, a positive test result for lupus anticoagulants using
a standard method, or a false-positive test result for >6 months confirmed by
Treponema pallidum immobilization or fluorescent treponemal antibody
absorption test)
Positive antinuclear autoantibody
• An abnormal titre of antinuclear autoantibody by immunofluorescence or an
equivalent assay at any point in time and in the absence of drugs
For the 1982 American College of Rheumatology (ACR) revised classification criteria see
REF. 95. For the 1997 update of the 1982 ACR revised classification criteria see REF. 96.
*Only one parameter needs to be present. Adapted with permission from REF. 96,
John Wiley and Sons.
SLICC classifi­cation criteria for SLE in 2012 (REF. 98).
With the current SLICC classification criteria, it is pos-
sible to meet the classification criteria with 4 of the 17
criteria (including at least one clinical and one immuno­
logical ­criterion) or biopsy-proven lupus nephritis in
the presence of ANAs or anti-dsDNA autoantibodies.
Unfortunately, with the wide range of SLE manifesta-
tions covered by the SLICC classification criteria and
despite the increase in the sensitivity to 97% (compared
with 86% for ACR classification criteria), the specificity
has dropped to 84% (compared with 94% for the ACR
classifi­cation criteria)97,98. One study showed that, of
2,055 patients with SLE from 17 centres in the Portuguese
and Spanish national registries, 296 patients did not
fulfil the ACR 1997 criteria; however, 63% of those did
meet the SLICC classification criteria102. The increased
sensitivity gives the SLICC classification ­criteria greater
validity, but the loss in specificity compromises them as
classification criteria99. However, the SLICC classification
criteria clearly have not made considerable improvement
compared with the existing ACR classification criteria in
identifying patients with early disease other than for renal
disease as an isolated clinical manifest­ation. The use of
one of these sets of criteria over the other remains to be
tested in future trials and research studies103.
Assessment of disease activity
The assessment of disease activity is challenging because
of the multifaceted complexity of the clinical presenta-
tions and their variation over time. Thus, at least in clin-
ical trials and research settings, the use of instruments
is essential for a standardized assessment of the disease
activity to enable comparison between different centres
and to monitor patients reliably. For this purpose, several
instruments have been developed and validated104 (BOX 5).
The ability to measure disease activity also facilitates
the management of the disease in patients. It is also known
that severe disease activity at presentation (a SLEDAI‑2K
score of ≥20) is a prognostic factor associated with mortal­
ity 105. Standardized definitions of clinically meaningful
change in disease activity (that is, remission, worsening
or flare, improvement and persistent active disease) have
been developed and validated104. Prolonged remission
(inactive disease) is an infrequent outcome and only
occurs in ~2.4% of patients with SLE without treat-
ment106. Patients who manifest a prolonged serologically
active (high anti-dsDNA antibodies or low complement
values) and clinically quiescent (SACQ) period require
no specific treatment during this period and accrue less
damage over a decade than matched controls. However,
close surveillance is warranted for this group107. More
recently, a consensus definition of lupus low disease activ-
ity (LLDAS) has been developed, but this requires further
external validation108.
In 1996, the SLICC group, in collaboration with the
ACR, developed the SLICC ACR Damage Index (SDI)109,
which measures the accumulation of organ damage
that has occurred since the onset of SLE. The SDI has
been shown to be valid and reliable110 and is accepted
as an independent outcome measure111. Damage in SLE
­predicts future damage accrual and mortality 112.

10 | 2016 | VOLUME 2 www.nature.com/nrdp

©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
 PRIMER

of patients with SLE118. Risk factors for low bone mineral

Figure 3 | Typical malar rash in a patient with SLE. Malar Naturerash (or butterfly
Reviews rash)
| Disease
Primers
typical skin complication found in up to 50% of patients with systemic lupus
erythematosus (SLE) and might be an indication of a flare in some. The rash
characteristically spares the nasolabial folds, allowing it to be distinguished in some
cases from other similar rashes, such as rosacea. Treatment is aimed at suppressing SLE
disease activity with drugs such as hydroxychloroquine, but topical treatment with
glucocorticoids or tacrolimus is also used.
density can be grouped into two main categories: non-SLE
disease-related factors (sociodemographic factors) and
SLE disease-related factors (which include disease activity,
the use of glucocorticoids, limited activity secondary to
arthritis and potential increased risk of fall s­ econdary
to myositis, among other factors)118. Identification of
such factors is essential for risk stratification and for the
develop­ment of preventive measures against low bone
mineral density in the future.
Cognitive impairment is one of the most common
manifestations of neuropsychiatric SLE with frequen-
cies of up to 80% reported119. A wide variation in the
prevalence of cognitive impairment has been reported,
is a
owing to the lack of standardized definitions and valid
metrics of cognitive impairment 120. The pathogenetic
mech­anisms of SLE-associated cognitive impairment are
unclear, but cognitive impairment requires early diagno-
sis and the development of interventions to prevent the
accrual of long-term damage and disability.

Comorbidities
As much as early diagnosis of SLE is important to initiate
the appropriate treatment and to prevent damage, cap-
turing flares is also important. This can only be achieved
when patients are having regular follow-up visits every
2–6 months regardless of the disease state of SLE113.
Besides the assessment of SLE disease activity, optimal
care for patients with SLE should incorporate surveillance
for the development of comorbidities and tissue damage.
These comorbidities can be the direct consequence of SLE
(especially chronic kidney disease and atherosclerosis) or
can be the consequence of SLE medication, especially
glucocorticoids, which might result in cataract, low bone
density, osteonecrosis and secondary diabetes, and/or
immunosuppressants, which might lead to recurrent
infections, premature menopause and hospitalizations.
Substantial progress has been made in the awareness
of accelerated atherosclerosis in patients with SLE. SLE
as a risk factor for atherosclerosis has been incorporated
into the American Heart Association guidelines for the
prevention of CVD in women114. The prevalence of coro­
nary artery disease in different cohorts, including the
Toronto SLE Clinic, was 6–11% and subclinical carotid
plaque development was reported in 30–50% of patients
with SLE115. Therefore, early identification of patients with
SLE at increased risk for premature CVD is crucial to the
development and implementation of effective prevention
strategies in this population.
Patients with SLE have an increased cancer risk,
particu­larly haematological cancers, cervical cancer, breast
cancer and lung cancer 116. The European League Against
Rheumatism (EULAR) recommended that patients
should follow cancer screening that is r­ ecommended for
the general population117.
Patients with SLE are at a high risk of developing
osteo­necrosis, which might result in pain. Diagnosis
of ­osteonecrosis involves radiographs, bone scans, tomo-
grams or magnetic resonance images (FIG. 4). Osteopenia
has been reported in 25–74% and osteoporosis in 1.4–68%
Management
When managing SLE, physicians must consider several
objectives simultaneously, but three are particularly
important: first, controlling the patients symptoms to
prevent immediate consequences and to improve quality
of life (QOL); second, minimizing damage due to disease
activity; and last, preventing long-term morbidity and
mortality. The currently available treatments for SLE do
not always allow us to achieve these objectives simulta-
neously, but judicious use and a targeted approach can
achieve good results in the majority of patients (TABLE 3).
Initial management of active non-renal SLE
For patients with considerably active SLE, the immediate
need is to achieve control over the inflammatory pro-
cess. The intensity of treatment is adjusted to the sever-
ity of the disease manifestations. Milder skin rashes are
often managed with sun avoidance, including the use
of high-factor (sun protection factor 50) sunblock or
sun-protective clothing. Topical glucocorticoids or top-
ical tacrolimus (a macrolide calcineurin inhibitor with
Box 5 | Disease activity scores in SLE
Two types of measures have been developed for the
assessment of disease activity in lupus. Global indices
describe the overall burden of inflammatory disease
(that is, the Systemic Lupus Erythematosus (SLE) Disease
Activity Index (SLEDAI)186 and its revisions100,187,188) and
organ-specific indices can be individual or incorporated
into one summary score (for example, the British Isles
Lupus Assessment Group (BILAG) criteria and its
revision189,190). More recently, new indices have been
developed that are sensitive to partial improvement in
disease activity (for example, the SLEDAI‑2000 Responder
Index‑50 (REF. 191)) and the use of composite indices in
drug trials (for example, the SLE Responder Index192 and
BILAG-based Composite Lupus Assessment180). A measure
to summarize disease activity over time — the Adjusted
Mean SLEDAI‑2000 (AMS) — has also been developed193.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 11

©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

a b c Although evidence for their efficacy in renal lupus

is stronger, agents including azathioprine (a purine
­analogue that blocks immune cell proliferation) or
mycophenolate mofetil (an inhibitor of purine synthe-
sis that blocks immune cell proliferation) are often co‑­
prescribed with antimalarials in non-renal SLE. However,
because immunosuppression can cause adverse effects,
including bone marrow suppression or liver test abnor-
malities, blood tests must be monitored during use for
these changes.

Figure 4 | Multifocal osteonecrosis in a patient with SLE following

Nature Reviewslong-term
| Disease Primers
corticosteroid treatment. MRI scans showing typical serpiginous osteonecrosis in the
left knee (part a; arrow), right knee (part b; arrows) and shoulder (part c; arrow).
Osteonecrosis in young patients with systemic lupus erythematosus (SLE) is an important
comorbidity as MRI is needed to confirm diagnosis in early stages and joint replacements
might be required in advanced stages. The management of SLE-associated bone disease
is to try to reduce glucocorticoid exposure while ensuring adequate control of SLE.
Intravenous iloprost (a vasodilator) and bisphosphonates (bone resorption inhibitors)
have successfully been used in early osteonecrosis.
immunosuppressive action) are used if problems persist.
Mild-to-moderate arthritis or pleurisy that causes chest
pains are usually treated with NSAIDs121.
More-severe SLE disease activity often requires sys-
temic glucocorticoids as initiation therapy with the
addition of maintenance immunosuppressive therapy in
the longer term to permit glucocorticoid dose tapering.
The optimal dose of glucocorticoids as initiation ther-
apy ­varies in practice. Minimizing total dosage is vital
to prevent signifi­cant steroid-induced comorbidities,
yet undertreatment can lead to insufficient immuno-
suppression and tissue damage accrual. More-persistent
or severe joint or skin involvement often involves using
oral prednisolone (<0.5 mg per kg) while intravenous
methyl­prednisolone can be used for more-aggressive
­neuropsychiatric or skin manifestations.
Maintenance treatment of non-renal SLE
To permit steroid tapering over the following weeks or
months (dependent on response) and to prevent the
high risk of relapse, immunosuppressive therapy is
­initiated in the early stages of glucocorticoid treatment.
This is because, unlike glucocorticoids, many immuno-
suppressive agents require weeks to become effective.
Antimalarials that are used for their immunosuppressive
actions, for example, hydroxychloroquine or, less com-
monly, quinacrine (also known as mepacrine) or chloro-
quine, are commenced immediately. The LUMINA study
suggested that hydroxychloroquine is well tolerated and
is associated with prolonged lifespan122, effects that are
potentially mediated by reducing flares123, and damage
accrual. Hydroxychloroquine may also reduce the risk of
incident diabetes mellitus in a dose-dependent manner 124.
Hydroxychloroquine is effective against cutaneous lupus
and might have other clinical benefits, such as improve-
ment of arthralgias and fatigue. Some experts recommend
that antimalarials should be used for all patients with
SLE unless there are contraindications. Potential retinal
­toxicity, albeit rare, requires ophthalmological monitoring
with long-term use.
Refractory non-renal SLE
Belimumab — a humanized recombinant IgG mono-
clonal antibody directed against BAFF — is licensed
for the treatment of patients with ‘active SLE despite
conventional therapy’ (REF. 125). Current SLE activity
indices might be inappropriate to monitor the efficacy
of belimumab, as the drug is effective but has a slow
onset of action. Although the exact role of belimumab in
SLE management remains to be determined, subgroup
analyses of the belimumab trials (BLISS I and BLISS II)
showed that the drug has greater therapeutic benefit in
patients with higher disease activity, anti-dsDNA positiv-
ity and low complement levels than in patients with SLE
with lower levels of these markers125. One concern is that,
although licensed for SLE, belimumab has not received
approval from funding bodies in some countries, which
might limit its use. Although well tolerated with no
significant adverse events over conventional therapy,
prescription requires tailored assessment of the overall
course of the disease, including past degree of activ-
ity, recent flare frequency, the dose of glucocorticoids
that is required to control the disease and the degree of
response to conventional agents. A subcutaneous version
of ­belimumab is undergoing phase III testing 126.
Management of specific features of SLE
Several other drugs have been used in the management of
additional SLE features, with limited evidence supporting
their use. Treatment of patients with SLE with DHEA,
a corticosteroid intermediate in the biosynthesis of andro-
gens and oestrogens, can improve overall disease activ-
ity and enable reduction in glucocorticoid dosage with
minor adverse effects of hirsutism (excessive hairiness)
or acne127. However, this drug is not licensed for SLE.
Haematological SLE manifestations including refractory
thrombocytopaenia or haemolytic anaemia can improve
with the semi-synthetic androgen analogue danazol128.
Thalidomide (an immunomodulatory drug) has success-
fully been used in the treatment of cutaneous lupus129, but
shows toxicity (especially peripheral neuropathy) and is
contraindicated in women of childbearing age.
While fatigue, joint pains, muscle aches and cogni-
tive symptoms are common in patients with SLE, they do
not always represent disease activity. These symptoms are
similar to fibromyalgia, which may coexist with SLE130.
Complicating the clinical picture, thyroid dysfunction131,
headaches and depression are all over-represented in
patients with SLE and require differentiation from SLE
disease activity before treatment is tailored. Treatments
aimed at controlling SLE activity do not always act against

12 | 2016 | VOLUME 2 www.nature.com/nrdp

©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
 PRIMER

these associated symptoms, and use of other thera­pies
such as centrally acting pain-modulating agents and
antidepressants may be required. In particular, fatigue
can be very resistant to treatment with non-drug thera­
pies, particularly aerobic exercise, which is ­important in
combatting this.
Management of active lupus nephritis
The best-studied SLE manifestation is lupus neph­ritis,
primarily because of its profound historical effect on
mortality and morbidity. Regimes commonly use a
short-term initiation and longer follow‑up maintenance
regime. While higher-dose initiation glucocorticoid

Table 3 | A selection of the targeted therapies used in SLE

Therapy Mechanism of action Outcome
T cells
T cell vaccination Depletion of autoreactive Improved SLEDAI score and SLE remission in refractory SLE
(immunization with inactivated T cells
autoreactive T cells)194
B cells
Rituxilup (a combination Chimeric anti‑CD20 antibody Remission of lupus nephritis in an open-label study
of rituximab and a single (B cell depletion)
intravenous dose of
corticosteroids, followed by
mycophenolate mofetil)137
Rituximab (LUNAR trial)142 Chimeric anti‑CD20 antibody RCT showed no difference between rituximab and placebo when used with
(B cell depletion) standard of care in class III and class IV lupus nephritis. Potential racial variation:
better response in African and Hispanic patients than in Caucasian patients
Ocrelizumab195 Human anti‑CD20 antibody Study discontinued owing to high rate of infection
(B cell depletion)
Epratuzumab180,181 Anti‑CD22 antibody Phase IIb study that suggested improvements in BILAG-based end point
(inhibits B cell receptor combined lupus assessment, but recent phase III data cast doubt on efficacy
signalling) over conventional treatment
Belimumab125 Inhibitor of BAFF Significant reduction in SELENA-SLEDAI scores versus controls on conventional
(also known as TNFSF13B) treatment
Atacicept196 Blockade of BAFF and APRIL 75 mg of atacicept did not improve flare or flare rate compared with placebo;
(also known as TNFSF13) a trial testing higher doses (150 mg) was terminated owing to two deaths
Blisibimod197 Blockade of BAFF Phase II trial of patients with SLE (a SLEDAI score of ≥6) showed improvements
with the highest dose of blisibimod and pooled placebo reached a >5 point
improvement in the SELENA-SLEDAI score
Tabalumab198 Blockade of BAFF Mixed results in two phase III trials and drug development discontinued by the
pharmaceutical company
dsDNA
Abetimus sodium (LJP 394)199 Crosslinks dsDNA receptor on Intention-to‑treat analysis showed no difference in frequency or time to
B cells renal flare
Cytokines
Infliximab200 TNF inhibitor Improvement in lupus nephritis measured by 50% improvement in proteinuria, as
seen in seven of nine patients, with benefits lasting up to 4 years after four infusions
Anakinra201 IL‑1 inhibitor Uncontrolled open-label study showed improvement in tender joints with
subsequent worsening
Sirukumab and PF‑04236921 Blockade of IL‑6 signalling Mixed results: sirukumab was associated with infections and drug development
(REF. 202) was stopped; PF‑04236921 showed good effects and further studies are in progress
Anti‑IL‑10 and B-N10 Inhibition of IL‑10 signalling Small (six patients) uncontrolled study showed mild improvement in the SLEDAI
(REF. 203) (suppression of TH1 response) score from 8 to 3
Sifalimumab204 Suppression of IFNα activity and Reduction in disease activity across several measures in a phase IIb study
attenuation of other cytokines
Anifrolumab205 Antagonist of IFNα receptor 1, Phase II RCT of 305 treatment-resistant patients with SLE demonstrated
which binds sterically to the significant improvement in primary composite end points of SRI and a reduction
IFN receptor, preventing in corticosteroid usage
the formation of a ternary
signalling complex
Promising results with sifalimumab and anifrolumab are mirrored by disappointing results with anti‑IL‑10 that targets double-stranded DNA (dsDNA) and
epratuzumab. The failure of many studies to reach end points shows the difficulty in obtaining a homogenous population of patients with SLE. The modification of
the Systemic Lupus Erythematosus (SLE) Disease Activity Index (SLEDAI) criteria in the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)
trial is referred to as the SELENA-SLEDAI score. APRIL, a proliferation-inducing ligand; BAFF, B cell-activating factor; BILAG, British Isles Lupus Assessment Group;
IFN, interferon; RCT, randomized controlled trial; SRI, SLE Responder Index; TH1, T helper 1; TNF, tumour necrosis factor.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 13

©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

regimes were historically used and may still be required
in resistant disease, lower-dose regimes may be as
effective, even in renal SLE. These are likely to become
standard practice in future because they may reduce
glucocorticoid-­associated comorbidities132–134. Patients
with lupus nephritis who are treated with lower-dose
glucocorticoids do not have worse symptoms than
patients given higher doses in a historical cohort 135.
In another open-label study of 42 patients with SLE
with active proliferative lupus nephritis, a starting dose
of 0.5 mg per kg daily of prednisone was equally effective
as 1 mg per kg daily when combined with the immuno­
suppressive mycophenolate mofetil136. Perhaps most
intriguingly, Condon et al.137 suggested that initiation
treatment of proliferative lupus nephritis with rituximab
(a B cell-specific antibody) and only a single pulse of
intravenous glucocorticoid followed by mycophenolate
mofetil maintenance is highly effective. This protocol
is dubbed ‘rituxilup’ and is currently being tested in a
controlled trial.
The best-studied forms of lupus nephritis are
the more-severe types, classified according to the
International Society of Nephrology–Renal Pathological
Society modification of the WHO criteria as class III,
class IV and class V. These require more-aggressive
treatment to prevent progression to dialysis and early
mortality, which was a key issue with lupus nephritis
in the 1950s up until the 1970s. Historically, treatment
with a combination of glucocorticoids and intravenous
cyclophosphamide (a chemotoxic alkylating agent) was
preferred138. In 2002, the Euro-Lupus randomized trial
of 90 patients with SLE with proliferative glomerulo­
nephritis demonstrated that a reduced-dosage cyclo-
phosphamide regimen followed by azathioprine was as
effective as higher-dose intravenous cyclop­hosphamide,
but was associated with considerably less tox­icity 139.
Later trials demonstrated that mycophenolate mofetil
was at least as effective for the treatment of lupus neph­
ritis as cyclophosphamide138. The 10‑year follow-up of
the Euro-Lupus low-dose cyclophosphamide cohort
demonstrated similar outcomes to the high-dose cyclo-
phosphamide group140. While glucocorticoid initiation
remains ‘best practice’, with the evidence to date, addi-
tional ­initiation therapy with mycophenolate mofetil
is now an established option, with intravenous cyclo­
phosphamide or rituximab as alternatives. Maintenance
treatment with mycophenolate mofetil or azathioprine is
most ­commonly used thereafter.
Rituximab remains an enigma because several case
reports have suggested benefit in case series of resistant
lupus nephritis after standard treatment with a range of
immunosuppressants141. Despite this, the 52‑week ran­
domized, double-blind LUNAR clinical trial of ritux­
imab in 144 patients with SLE with class III or class IV
lupus nephritis showed no significant difference in the
primary end point of complete or partial renal response
defined by features including serum creatinine levels,
proteinuria and active urinary sediment 142. There is
debate about whether the trial was underpowered and
whether trial design was compromised by the fact that
rituximab was an addition rather than a replacement
to conventional therapy including mycophenolate
mofetil143. The investigator-initiated, randomized RING
trial is currently addressing whether the addition of
rituximab to standard of care with azathioprine, myco-
phenolate mofetil or intravenous cyclophosphamide
improves renal response rate after 104 weeks144.
Following the initial ‘induction’ phase of treatment
of lupus nephritis, maintenance therapy is usually given
for at least 2–3 years with azathioprine or mycophenolate
mofetil, the latter being slightly more efficacious with
fewer relapses145,146. Angiotensin-converting enzyme
inhibitors or angiotensin receptor antagonists are often
used as renoprotective agents. Additional therapeutic
options that can be considered are the use of intra-
venous immunoglobulin, which probably works by
interfering with B cell, T cell and antibody function, or
plasma exchange, which aims to remove pathogenetic
antibodies from the circulation. These methods are use-
ful particularly when infection may preclude the use of
­immunosuppressive agents147.
Quality of life
SLE can exert a profound effect on the life of patients,
both qualitative and quantitative, with higher mortal-
ity rates than the general population. Compared with
healthy controls, patients with SLE report lower levels of
vitality and general health, with a marked effect of SLE
on physical functioning, psychological and emotional
status and social life148. The physical and mental compo-
nents of the 36‑Item Short-Form Health Survey (SF‑36)
— a general QOL indicator — have been consistently
reduced in patients with SLE compared with controls.
A large number of patients with SLE report tiredness,
pain, exacerbation, anxiety about the condition and
exacerbations, inability to carry out daily tasks and fear
of physical disability 148. A study in California showed
a progressive decline in the proportion of patients
with SLE who were employed between 2002 and 2004
(REF. 149). While 74% of patients with SLE were work-
ing at the time of diagnosis, only 55% were employed
at the time of the survey, an average of 12 years later.
A progressive decline in working hours among those
employed was seen: 1,105,401 total hours worked among
those employed in the year of their diagnosis, 746,982
hours at the baseline interview and 654,480 hours a
year later. Although there was no control group in the
study, all respondants were <65 years of age at the time
of the survey. In addition, in Europe, a negative effect
on produc­tivity and professional development has been
found using a survey of 2,070 patients with SLE150.
Several scales have been used to measure
the health-related QOL of patients with SLE. Besides the
generic SF‑36 questionnaire, SLE-specific instruments
have been proposed: the Lupus QOL (LupusQOL),
the Systemic Lupus Erythematosus-Specific QOL
Questionnaire (SLEQOL) and the Systemic Lupus
Erythematosus QOL Questionnaire (L‑QOL). These
instruments have been recently reviewed151.
Whichever scale is used, some SLE-related issues
consistently correlate with a decline in QOL of the
patient (TABLE 4). Both SLE activity and irreversible organ

14 | 2016 | VOLUME 2 www.nature.com/nrdp

©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.

Table 4 | Outcome measures used to examine quality of life in SLE
Aim of study
Fatigue
To determine the link between affective states,
personality traits and mental health status
with SLE-associated fatigue in 57 Caucasian
patients206
To determine the best instruments to assess
fatigue in SLE207
Mental and cognitive health
Comparison of patients with SLE, multiple
sclerosis, rheumatoid arthritis and healthy
controls, using the ANAM score, which is
sensitive to cognitive impairment208
To compare changes in QOL in 715 patients with
SLE from three countries (the United States,
Canada and the United Kingdom) over 4 years209
Physical functioning
To assess if disease activity was associated with
physical functioning in 96 patients with SLE210
To determine baseline factors that are predictive
of HR‑QOL211
To assess a total of 552 patients with SLE using
SF‑6D (a self-reported measure of HR‑QOL),
which produces a single numerical value212
Work disability
Several self-reported and assessed variables
including poverty, education, sex, race and
disease activity measured in 273 patients with
SLE in the LUMINA cohort213
Systematic review with the aim of overcoming
limitations owing to small sample size in some
studies. Data was extracted with respect to
patient characteristics, disease measures, work
disability and employment rates214
Costs
Estimation of cumulative indirect health care
costs over 4 years in 715 patients with SLE in
three countries (the United States, Canada
and the United Kingdom)215
Evaluation of direct health care costs of 109
patients with active SLE in three Canadian
centres over 2 years216
ANAM, Automated Psychological Assessment Metrics; FFS, Fatigue Severity Scale; HAQ, Health Assessment Questionnaire; HR-QOL, health-related quality of life;
SF‑6D, Short-Form 6D; SF‑36, 36‑Item Short-Form Health Survey; SLAM, Systemic Lupus Activity Measure; SLAM-R, SLAM revised; SLE, systemic lupus
erythematosus; SLEDAI, SLE Disease Activity Index; SLICC, Systemic Lupus International Collaborating Clinics.
NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 15
PRIMER
Findings Measures and instruments
Psychological distress and personality trait FSS, Personality defined with Minnesota
patterns in SLE-associated fatigue similar to Multiphasic Personality Inventory 2 and mental
patients with chronic pain. Depression was status by Beck Depression Inventory
significantly associated with fatigue
Using literature searches and consensus Several fatigue instruments including SLAM,
opinion from experts, 15 fatigue instruments FSS and SLEDAI
were reviewed. The FSS was most commonly
used and validated in several studies with
internal responsiveness, construct validity
and consistency
Patients with SLE show similar cognitive ANAM
impairment to patients with rheumatoid
arthritis, but less than patients with multiple
sclerosis using the ANAM subsets designed
to assess cognitive tasks via response time
and accuracy
While patients with SLE in the United States SF‑36 physical and mental component scores
incurred higher health care costs, there was
no difference in changes to mental or physical
scores between countries or of damage accrual
HAQ and SF‑36 were correlated with disease HAQ
activity determined by damage indices (SLICC)
and disease activity (SLEDAI), and SLAM‑R.
HAQ correlated with SLAM‑R but not SLEDAI,
suggesting differences in the degree to which
patient reports vary between measures
Total of 346 patients with SLE (1,351 patient SF‑36
visits) suggested that lower baseline
HR‑QOL predicted future lower HR‑QOL
with little relation to organ damage accrual
or disease activity
SF‑6D predicts damage accrual but not SF‑6D
mortality in patients with SLE
Rate of self-reported work disability was 19% Several indices including illness behaviours,
at 5 years and was higher for African-American learned helplessness (Rheumatology Attitude
individuals (25%) possibly owing to higher Index), social support (Support Evaluation List),
damage accrual and poverty compared with SF‑36, Pain Visual Analogue Score, HR‑QOL
Caucasian individuals and Hispanic individuals and the Arthritis Self-Efficacy Scale
26 studies representing 9,886 patients with Systematic review of 135 titles from the United
SLE were included. About 32.5% of patients States, Canada, the United Kingdom and
were work disabled. Reduced employment was Sweden, among others
owing to cessation of work rather than reduced
hours and was associated with several factors,
such as race, education and disease activity
Indirect costs represent up to 74% of total Several measures including lost productivity,
health care-related costs. They are higher in disease activity and social support
the United States than in the United Kingdom
and Canada but are not associated with
better outcomes
Direct health care costs correlate with worse Retrospective analysis of medical records. Flare
disease activity and are mainly owing to activity (SLEDAI Flare Index), disease activity
hospitalizations and medications (SLEDAI), tissue damage (SLICC) and health
care use were measured
©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

Box 6 | Proposed remission grades in SLE*
Grade A: complete remission
• Systemic Lupus Erythematosus (SLE) Disease Activity
Index‑2000 score of 0
• No serological disease activity
• No clinical disease activity
• Glucocorticoid and immunosuppressant free
Grade B: clinical remission off glucocorticoids
• Serologically active disease activity
• Clinically quiescent disease
• Glucocorticoid free
• Use of immunosuppressants is allowed
Grade C: clinical remission on glucocorticoids
• Serologically active disease activity
• Clinically quiescent disease
• Use of glucocorticoids is allowed (<5 mg daily)
• Use of immunosuppressants is allowed
*See REF. 176.
damage are important predictors of worse QOL148,152.
Fatigue affects QOL profoundly 148,153 and is present in up
to 80% of patients with SLE153. Fatigue, often perceived
as a feature of active lupus, is a multifactorial symptom
with a questionable relationship with disease activity 154.
Other factors that potentially contribute to fatigue are
obesity, low physical activity, poor sleep quality, mood
disorders, cognitive dysfunction, anxiety and vitamin D
deficiency 154. Although fatigue is often recalcitrant, stud-
ies suggest that treatment with calcifediol (a vitamin D
precursor) results in a small but significant reduction
in fatigue in patients with vitamin D‑deficient SLE155.
In addition, post hoc analysis of randomized controlled
trials of belimumab have shown a decreased degree of
fatigue among responders156, although this drug cannot
be recommended exclusively for the treatment of SLE-
associated fatigue. Recently, a study of 1,827 patients
from the SLICC cohort confirmed the effect of mood
disorders on the QOL of patients with SLE157.
It is important to remember that many drugs
used to treat SLE can cause serious adverse effects,
particularly glucocorticoids. Moreover, the marked
changes in phys­ical appearance caused by steroid ther-
apy can be devastat­ing, particularly in young female
patients158. Thus, it is not surprising that glucocorti-
coids are consistently identified as one of the major
predictors of decreased QOL148,153. While lowering
gluco­corticoid doses is strongly recommended, treat-
ing fatigue and depression while still ensuring sufficient
­immunosuppression can be challenging.
Outlook
Prevention
SLE comes at a physical, social and economic cost. Up to
30% of patients with SLE receive disability benefits and
perhaps 20% of patients cease employment 10 years
after diagnosis159. Several parts of the immune system
can be dysfunctional. Although the focus in recent
years has been on developing new-targeted therapies,
simpler, more cost-effective strategies might already
exist. Moreover, although prevention infers reducing the
chance of getting the disease, it must also be aimed at
reducing the chance of damage accrual once the disease
is identified.
Specific autoantibodies can be detected in patients
9 years before the diagnosis of SLE (mean: 3.3 years)160.
In addition, ANA positivity is found in 78% and
dsDNA-­specific antibodies in 55% of future patients
with SLE, which presents an opportunity for primary
prevention. One study found that patients treated with
hydroxychloro­quine or glucocorticoids early in disease
development had a delayed onset of a formal SLE diagno-
sis, which required four or more ACR criteria161 (BOX 4).
Early identification of symptoms is paramount if this
strategy is to work.
Identificaton of damage
Although overall SLE-associated mortality has improved
with 10‑year survival of 63% in the 1950s to 91% in 2000,
this disguises a slowdown in mortality improvement
after the 1980s10. To overcome this slowdown, there is
a need to improve identification and management of
both renal and neuropsychiatric lupus in particular. As a
result, long-term survival in SLE remains poor 162.
Future strategies should include the early detection of
damage. Potential biomarkers include urinary ­levels
of VCAM1, which correlates with proliferative and
membranous glomerulonephritis, proteinuria and renal
damage163 as well as disease activity 91. Other urinary bio-
markers including TNF-like weak inducer of apoptosis
(TWEAK, also known as TNFSF12) are also increased
in mouse models of SLE as well as in patients. TWEAK,
part of the TNF superfamily, acts proximally in the
induction of several nephritis-related cytokines, such as
CC-chemokine ligand 5 (CCL5) and CXC-chemokine
ligand 10 (CXCL10). Higher urinary levels of TWEAK
reflect renal flares of SLE and are found at lower levels in
non-renal flares and stable lupus nephritis164.
Diagnosing neuropsychiatric SLE remains a chal-
lenge. Functional MRI can detect certain phenotypes
including stroke. A subset of dsDNA-specific anti­
bodies cross-react with the extracellular ligand-binding
domain, comprising the NR2A and NR2B subunits of
the N‑methyl-d‑aspartate receptor. Although there is
no clear correlation between anti‑NR2 antibodies and
neuropsychiatric SLE, anti‑NR2 antibodies purified
from patients with neuropsychiatric SLE can induce
cognitive changes, memory deficit, neurotoxicity and
compromised blood–brain barrier in mice165,166.
The challenge is to translate these research tools to
bedside tests that can rapidly identify ‘at-risk’ patients
with SLE to prevent organ damage and prolong lifespan
and QOL.
Management of cardiovascular complications
An increased risk of CVD and early mortality is associ­
ated with SLE and especially longer SLE duration167.
The overall risk of CVD is estimated to be between 2.6
(REF. 168) and 10‑times higher 169 in patients with SLE than

16 | 2016 | VOLUME 2 www.nature.com/nrdp

©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
 PRIMER

in the general population, even allowing for traditional Treatment targets

risk factors. EULAR guidelines suggest that patients with Studies from various clinical conditions clearly demon-
SLE should be monitored for CVD risk. However, specific strate the benefit of disease-specific treatment targets.
recommendations cannot yet be made as we do not know An international task force recommended several prin-
which strategies are best to reduce the CVD burden in ciples of treat‑to‑target management in SLE; the target
SLE. It would make sense to identify patients at risk, con- for treatment should be remission, prevention of damage
trol disease activity and modify traditional risk ­factors, and disease flares and minimization of glucocorticoid
but longitudinal studies are lacking in this respect170. usage, among others173. Unlike rheumatoid arthritis,
Preventive strategies for CVD are likely to be b ­ etter measurement tools to define remission or prevention,
because patients with SLE have a higher in‑hospital such as BILAG or SLEDAI‑2K, are not widely used in
mortality and morbidity after coronary percutaneous clinical practice as they are perceived to be cumber-
intervention, even after adjustment for traditional risks some and time-consuming. In addition, the definition of
and comorbid conditions171. Complications such as the remission in SLE has not been validated, nor which vari­
‘lipid paradox’, in which CVD risk can be higher in those ables should be considered to define remission. Studies
with lower total and LDL cholesterol, only add to the point towards better outcomes using remission targets in
uncertainty of which parameters are best to modify 172. lupus nephritis, but these may not be applicable to other
facets of SLE because of its heterogeneity 174,175.
Three grades of remission have been suggested by
one group but have yet to be widely accepted176 (BOX 6).
A study in Caucasian patients found that, although com-
plete, prolonged remission (grade A) was possible in
Patient evaluation
Blood tests
7% of patients and significantly more patients achieved
ECG remission on medication with or without low-dose gluco-
Lung function test corticoids (~15% in each category (grade B and grade C)).
Chest X-ray
OGD and colonoscopy
Compared with previous studies using similar categories,
CT or PET the proportion of patients in SACQ remission, (grade B)
may have improved from 2.8% in a SLE cohort between
1970 and 1997 (REF. 177) to 14.7% in this study 176. The
reason for this is likely to be better management strat­
egies with the wider acceptance that ­controlling damage,
especially in renal SLE, is paramount.
Mobilization of stem cells Important questions for the future are how long
With intravenous cyclophosphamide and GM-CSF remission must last for before patients can come off
medication and what the impact of long-term remission
on target organ damage and mortality is.
Conditioning regimen Collection of CD34+ stem cells
Intravenous cyclophosphamide Via apheresis Future therapies
and rabbit anti-thymocyte globulin
Recently an expert panel has developed treat‑to‑­target
guidance for SLE173,178. This is complicated for SLE
Stem cell storage
Liquid nitrogen and DMSO until use because, in contrast to other diseases, the heterogeneity
of the condition means that several therapeutic targets
may have to be considered simultaneously.
Thaw stem cells
Only one therapy has been approved or licensed
for use in SLE in the past 60 years (that is, belimumab)
and none are currently being considered for approval.
Clinical trials in SLE have been hampered by compro-
mised trial design and unexpected results. Rituximab
Injection of stem cells
Antibiotics was feted as an effective targeted drug for lupus neph­
Antivirals ritis, but the LUNAR and EXPLORER trials did not meet
Antifungals end points for significance143. Trial design was compro-
Engraftment for 10–14 days
mised by factors such as steroid usage and very s­ tringent
end points that may have led to an u ­ nderestimation
of effect.
Guidance on drug development trials in SLE was
Figure 5 | Stem cell transplantation in SLE. Stem cell transplantation has been used ­produced in 2010 by the US FDA179. However, future t­ rials
Nature Reviews | Disease Primers
in mouse models of systemic lupus erythematosus (SLE) and in patients who failed
must address the issues of disease prevention and early
conventional treatments and biologics. Conventionally, haematopoeitic stem cells
have been used, but the multipotent mesenchymal stem cells from bone marrow, intervention to prevent damage accrual. Encouraging
which normally make cartilage, bone and adipose tissue, might reduce the need the use of organ-specific measures, such as Cutaneous
for myeloablative therapy in refractory SLE in future. DMSO, dimethyl sulfoxide; Lupus Erythematosus Disease Area and Severity
ECG, electrocardiogram; GM‑CSF, granulocyte–macrophage colony-stimulating factor; Index (CLASI) for skin, and specific QOL measures,
OGD, oesophagogastroduodenoscopy. such as Lupus Patient-Reported Outcome (LupusPRO)

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 17

©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

or LupusQOL, will overcome some of the reservations
about ­heterogeneity of the disease.
Despite the unexpected results in some trials, an
impressive number of novel agents are currently in
clinical development for SLE, including the B cell-­
modulating agent epratuzumab (anti‑CD22)180, IFN
antagonists and IL‑6 and IL‑10 blockers (TABLE 3). While
two phase III trials with epratuzumab181 failed to achieve
their primary end points, there is still hope that with fur-
ther trials and analyses, patient subgroups may respond
to these newer therapies, as happened with the LUNAR
trial of rituximab142.
Despite these issues, future therapies will usher in
a continuing era of biologic therapeutic agents that are
more targeted in their actions. New therapies should be
tailored to individuals in patient subgroups with distinct
clinical and serological features57. Future strategies must
also minimize the long-term effect of glucocorticoids.
Studies of rituximab in lupus nephritis point to how
this could work in practice137. Combination therapy of
targeted therapeutic agents might lead to synergistic
actions with clinical trials using combinations of ritux­
imab, belimumab and cyclophosphamide182. Innovations
include the construction of potentially effective novel
bispecific proteins183. Replacement of the dysfunctional
immune system with a normal one will be another fruit-
ful strategy. First, altering the SLE genotype through the
use of vectors (viral vectors or naked plasmids pack-
aged into liposomes) to deliver new genes into immune
cells or stem cells shows promise in mouse models of
SLE. Targets could include the cytokine genes IL2,
TGFβ, IFΝγ and the co-stimulatory molecule CTLA4
(REF. 184), while future human trials are awaited pend-
ing refinement of techniques to permit better outcomes
and fewer adverse events. Long-term remission and even
cure might be possible with either autologous stem cell
transplantations, despite high mortality risk185 (FIG. 5), or
mesenchymal stem cell procedures in which stem cells
are more-readily available and myeloablative treatment
is unnecessary and therefore potentially safer.
The challenge for the future is to clarify the key
mechanisms that initiate and perpetuate the disease.
Understanding these mechanisms will enable clinicians,
scientists and patients to achieve their common goal —
the cure from a disease that still causes considerable
morbidity and mortality.

1. Faurschou, M., Starklint, H., Halberg, P.
& Jacobsen, S. Prognostic factors in lupus nephritis:
diagnostic and therapeutic delay increases the risk of
terminal renal failure. J. Rheumatol. 33, 1563–1569
(2006).
2. Sullivan, K. E. Genetics of systemic lupus
erythematosus: clinical implications. Rheum. Dis. Clin.
North Am. 26, 1229–1256 (2000).
3. Moser, K. L., Kelly, J. A., Lessard, C. J. & Harley, J. B.
Recent insights into the genetic basis of systemic
lupus erythematosus. Genes Immun. 10, 373–379
(2009).
4. Tsokos, G. C. & Kammer, G. M. Molecular aberrations
in human systemic lupus erythematosus. Mol. Med.
Today 6, 418–424 (2000).
5. Deng, Y. & Tsao, B. Genetic susceptibility to systemic
lupus erythematosus in the genomic era. Nat. Rev.
Rheumatol. 6, 683–692 (2010).
6. Buyon, J. P. et al. The effect of combined estrogen and
progesterone hormone replacement therapy on
disease activity in systemic lupus erythematosus:
a randomized trial. Ann. Intern. Med. 142, 953–962
(2005).
SLE is more common in women than in men,
suggesting that hormonal factors might be
important in SLE pathogenesis. This study found
an increased risk of mild-to-moderate, but not
severe, SLE flare with hormone-replacement
therapy compared with placebo; this is a clinically
useful finding.
7. Chang, D. M., Lan, J. L., Lin, H. Y. & Luo, S. F.
Dehydroepiandrosterone treatment of women with
mild‑to‑moderate systemic lupus erythematosus:
a multicenter randomized, double-blind, placebo-
controlled trial. Arthritis Rheum. 46, 2924–2927
(2002).
8. Tektonidou, M. G., Laskari, K., Panagiotakos, D. B.
& Moutsopoulos, H. M. Risk factors for thrombosis
and primary thrombosis prevention in patients with
systemic lupus erythematosus with or without
antiphospholipid antibodies. Arthritis Rheum. 61,
2929–2936 (2009).
This study examined risk factors for thrombosis in
SLE. Significant risk factors included positive lupus
anticoagulant and anticardiolipin antibody profiles.
Aspirin and hydroxychloroquine had a protective
role against thrombosis in antiphospholipid
antibody-positive SLE, suggesting that these
are clinically useful drugs.
9. Mok, C. C., Tang, S., To, C. & Petri, M. Incidence
and risk factors of thromboembolism in systemic lupus
erythematosus: a comparison of three ethnic groups.
Arthritis Rheum. 52, 2774–2782 (2005).
10. Mak, A., Cheung, M. W. L., Chiew, H. J., Liu, Y.
& Ho, R.C. Global trend of survival and damage
of systemic lupus erythematosus: meta-analysis
and meta-regression of observational studies from
the 1950s to 2000s. Semin. Arthritis Rheum. 41,
2830–2839 (2012).
11. Quismorio, F. P. & Torralba, T. P. in Dubois Lupus
Erythematosus and Related Syndromes
(eds Wallace, D. J. & Hahn, B. H.) 526–540 (2013).
12. Castrejon, I. et al. Indices to assess patients with
systemic lupus erythematosus in clinical trials, long-
term observational studies, and clinical care. Clin. Exp.
Rheumatol. 32, S585–S595 (2014).
13. Kumar, K., Chambers, S. & Gordon, C. Challenges of
ethnicity in SLE. Best. Pract. Res. Clin. Rheumatol. 23,
549–561 (2009).
14. Pons-Estel, G. J., Alarcon, G. S., Scofield, L.,
Reinlib, L. & Cooper, G. S. Understanding the
epidemiology and progression of systemic lupus
erythematosus. Semin. Arthritis Rheum. 39,
257–268 (2010).
15. Lim, S. S. et al. The incidence and prevalence
of systemic lupus erythematosus, 2002–2004:
the Georgia Lupus Registry. Arthritis Rheumatol. 66,
357–368 (2014).
16. Somers, E. C. et al. Population-based incidence
and prevalence of systemic lupus erythematosus:
the Michigan Lupus Epidemiology and Surveillance
program. Arthritis Rheumatol. 66, 369–378 (2014).
17. Laustrup, H., Voss, A., Green, A. & Junker, P.
Occurrence of systemic lupus erythematosus in
a Danish community: an 8‑year prospective study.
Scand. J. Rheumatol. 38, 128–132 (2009).
18. Rees, F. et al. The incidence and prevalence of
systemic lupus erythematosus in the UK, 1999–2012.
Ann. Rheum. Dis. 75, 136–141 (2016).
19. Johnson, A. E., Gordon, C., Palmer, R. G.
& Bacon, P. A. The prevalence and incidence of
systemic lupus erythematosus in Birmingham,
England. Relationship to ethnicity and country of
birth. Arthritis Rheum. 38, 551–558 (1995).
20. Yee, C. S. et al. Birmingham SLE cohort: outcomes
of a large inception cohort followed for up to 21 years.
Rheumatology (Oxford) 54, 836–843 (2015).
21. Sexton, D. J. et al. ESRD from lupus nephritis in the
United States, 1995–2010. Clin. J. Am. Soc. Nephrol.
10, 251–259 (2015).
22. Flower, C., Hennis, A. J., Hambleton, I. R.,
Nicholson, G. D. & Liang, M. H. Systemic lupus
erythematosus in an African Caribbean population:
incidence, clinical manifestations, and survival in the
Barbados National Lupus Registry. Arthritis Care Res.
(Hoboken) 64, 1151–1158 (2012).
23. Ferucci, E. D. et al. Prevalence and incidence of
systemic lupus erythematosus in a population-based
registry of American Indian and Alaska native people,
2007–2009. Arthritis Rheumatol. 66, 2494–2502
(2014).
24. Segasothy, M. & Phillips, P. A. Systemic lupus
erythematosus in Aborigines and Caucasians in
central Australia: a comparative study. Lupus 10,
2439–2444 (2001).
25. Bossingham, D. Systemic lupus erythematosus in the
far north of Queensland. Lupus 12, 327–331 (2003).
26. Yeh, K. W., Yu, C. H., Chan, P. C., Horng, J. T.
& Huang, J. L. Burden of systemic lupus
erythematosus in Taiwan: a population-based survey.
Rheumatol. Int. 33, 1805–1811 (2013).
27. Ju, J. H. et al. Prevalence of systemic lupus
erythematosus in South Korea: an administrative
database study. J. Epidemiol. 24, 1295–1303 (2014).
28. Shim, J. S., Sung, Y. K., Joo, Y. B., Lee, H. S. & Bae, S. C.
Prevalence and incidence of systemic lupus
erythematosus in South Korea. Rheumatol. Int. 34,
909–917 (2014).
29. Yurkovich, M., Vostretsova, K., Chen, W.
& Avina‑Zubieta, J. A. Overall and cause-specific
mortality in patients with systemic lupus erythematosus:
a meta-analysis of observational studies. Arthritis Care
Res. (Hobeken) 66, 608–616 (2014).
This meta-analysis of published data from the
inception of Medline and EMBASE databases
to 2011 showed all-cause mortality was threefold
higher in patients with SLE than in the general
population. The highest mortality risk was
with renal SLE.
30. Mok, C. C., Kwok, R. C. & Yip, P. S. Effect of renal
disease on the standardized mortality ratio and life
expectancy of patients with systemic lupus
erythematosus. Arthritis Rheum. 65, 2154–2160
(2013).
31. Gonzalez, L. A., Toloza, S. M. & Alarcon, G. S.
Impact of race and ethnicity in the course and
outcome of systemic lupus erythematosus.
Rheum. Dis. Clin. North Am. 40, 2433–2438 (2014).
This paper provides a useful overview of how SLE
varies in its impact in different races, with
non-white races having higher mortality, higher
hospital admission rates and higher post-discharge
mortality than white races. Poverty and
socioeconomic status seem to be important factors
in this racial variation.
32. Gustafsson, J. T. et al. Risk factors for cardiovascular
mortality in patients with systemic lupus
erythematosus, a prospective cohort study.
Arthritis Res. Ther. 14, R46 (2012).

18 | 2016 | VOLUME 2 www.nature.com/nrdp

©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.

33. Crow, M. K., Olferiev, M. & Kirou, K. A. Targeting of
type I interferon in systemic autoimmune diseases.
Transl Res. 165, 296–305 (2015).
34. James, J. A. Clinical perspectives on lupus genetics:
advances and opportunities. Rheum. Dis. Clin.
North Am. 40, 413–432 (2014).
35. Truedsson, L. et al. Complement deficiencies and
systemic lupus erythematosus. Autoimmunity 40,
560–566 (2007).
36. Graham, R. R. et al. Specific combinations of
HLA‑DR2 and DR3 class II haplotypes contribute
graded risk for disease susceptibility and
autoantibodies in human SLE. Eur. J. Hum. Genet. 15,
823–830 (2007).
37. Price, P. et al. The genetic basis for the association of
the 8.1 ancestral haplotype (A1, B8, DR3) with
multiple immunopathological diseases. Immunol. Rev.
167, 257–274 (1999).
38. Santer, D. M. et al. C1q deficiency leads to the
defective suppression of IFN-α in response to
nucleoprotein containing immune complexes.
J. Immunol. 185, 4738–4749 (2010).
39. Crow, Y. J. & Manel, N. Aicardi–Goutières syndrome
and the type I interferonopathies. Nat. Rev. Immunol.
15, 4429–4440 (2015).
40. Namjou, B. et al. Evaluation of the TREX1 gene in a
large multi-ancestral lupus cohort. Genes Immun. 12,
270–279 (2011).
41. Niewold, T. B. et al. Association of the IRF5 risk
haplotype with high serum interferon-α activity
in systemic lupus erythematosus patients.
Arthritis Rheum. 58, 2481–2487 (2008).
42. Taylor, K. E. et al. Risk alleles for systemic lupus
erythematosus in a large case–control collection and
associations with clinical subphenotypes. PLoS Genet.
7, e1001311 (2011).
This study of 1,919 patients with SLE calculated
a genetic risk score determined by the number
of risk alleles. This study proposed three groups
of patients with SLE: those with cumulative, single
or no known associations with currently known
SLE loci.
43. Li, Q. Z. et al. The lupus-susceptibility gene
kallikrein downmodulates antibody-mediated
glomerulonephritis. Genes Immun. 10, 2503–2508
(2009).
44. Scofield, R. H. et al. Klinefelter’s syndrome (47,XXY) in
male systemic lupus erythematosus patients: support
for the notion of a gene-dose effect from the
X chromosome. Arthritis Rheum. 58, 2511–2517
(2008).
45. Costenbader, K. H., Feskanich, D., Stampfer, M. J.
& Karlson, E. W. Reproductive and menopausal factors
and risk of systemic lupus erythematosus in women.
Arthritis Rheum. 56, 1251–1262 (2007).
46. Kang, I. et al. Defective control of latent Epstein–Barr
virus infection in systemic lupus erythematosus.
J. Immunol. 172, 1287–1294 (2004).
47. Yadav, P. et al. Antibodies elicited in response to
EBNA‑1 may cross-react with dsDNA. PLoS ONE 6,
e14488 (2011).
48. Gorelik, G. et al. Impaired T cell protein kinase Cδ
activation decreases ERK pathway signaling in
idiopathic and hydralazine-induced lupus. J. Immunol.
179, 5553–5563 (2007).
49. Du, J. et al. DNA methylation pathways and their
crosstalk with histone methylation. Nat. Rev. Mol. Cell
Biol. 16, 5519–5532 (2015).
50. Costenbader, K. H. et al. Cigarette smoking and the
risk of systemic lupus erythematosus: a meta-analysis.
Arthritis Rheum. 50, 849–857 (2004).
51. Finckh, A. et al. Occupational silica and solvent
exposures and risk of systemic lupus erythematosus
in urban women. Arthritis Rheum. 54, 3648–3654
(2006).
52. Stetson, D. B. Endogenous retroelements and
autoimmune disease. Curr. Opin. Immunol. 24,
692–697 (2012).
53. Bennett, L. et al. Interferon and granulopoiesis
signatures in systemic lupus erythematosus blood.
J. Exp. Med. 197, 711–723 (2003).
54. Baechler, E. C. et al. Interferon-inducible gene
expression signature in peripheral blood cells of
patients with severe lupus. Proc. Natl Acad. Sci. USA
100, 2610–2615 (2003).
55. Crow, M. K., Kirou, K. A. & Wohlgemuth, J. Microarray
analysis of interferon-regulated genes in SLE.
Autoimmunity 36, 2481–2490 (2003).
56. Lovgren, T. et al. Induction of interferon-α production
in plasmacytoid dendritic cells by immune complexes
containing nucleic acid released by necrotic or late
NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 19
apoptotic cells and lupus IgG. Arthritis Rheum. 50,
1861–1872 (2004).
57. Kirou, K. A. et al. Activation of the interferon-α
pathway identifies a subgroup of systemic lupus
erythematosus patients with distinct serologic features
and active disease. Arthritis Rheum. 52, 1491–1503
(2005).
58. Christensen, S. R. et al. Toll-like receptor 7 and TLR9
dictate autoantibody specificity and have opposing
inflammatory and regulatory roles in a murine model
of lupus. Immunity 25, 1417–1428 (2006).
59. Barrat, F. J. et al. Nucleic acids of mammalian origin
can act as endogenous ligands for Toll-like receptors
and may promote systemic lupus erythematosus.
J. Exp. Med. 202, 1131–1139 (2005).
60. Oliveira, L. et al. Dysregulation of antiviral helicase
pathways in systemic lupus erythematosus.
Front. Genet. 5, 418 (2014).
61. Gao, D. et al. Activation of cyclic GMP–AMP synthase
by self-DNA causes autoimmune diseases. Proc. Natl
Acad. Sci. USA 112, E5699–E5705 (2015).
62. Villanueva, E. et al. Netting neutrophils induce
endothelial damage, infiltrate tissues, and expose
immuno­stimulatory molecules in systemic lupus
erythematosus. J. Immunol. 187, 538–552 (2011).
63. Crispin, J. C., Kyttaris, V. C., Terhorst, C.
& Tsokos, G. C. T cells as therapeutic targets in SLE.
Nat. Rev. Rheumatol. 6, 317–325 (2010).
64. Ettinger, R. et al. IL‑21 and BAFF/BLyS synergize in
stimulating plasma cell differentiation from a unique
population of human splenic memory B cells.
J. Immunol. 178, 2872–2882 (2007).
65. Koshy, M., Berger, D. & Crow, M. K. Increased
expression of CD40 ligand on systemic lupus
erythematosus lymphocytes. J. Clin. Invest. 98,
2826–2837 (1996).
66. Nambiar, M. P. et al. Reconstitution of deficient T cell
receptor ζ chain restores T cell signaling and
augments T cell receptor/CD3‑induced interleukin‑2
production in patients with systemic lupus
erythematosus. Arthritis Rheum. 48, 1948–1955
(2003).
67. Gergely, P. Jr et al. Mitochondrial hyperpolarization
and ATP depletion in patients with systemic lupus
erythematosus. Arthritis Rheum. 46, 175–190
(2002).
68. Coit, P. et al. Genome-wide DNA methylation study
suggests epigenetic accessibility and transcriptional
poising of interferon-regulated genes in naive CD4+
T cells from lupus patients. J. Autoimmun. 43, 78–84
(2013).
This study characterizes genome methylation in
samples from patients with SLE and demonstrates
that type I IFN-regulated genes comprise the
majority of hypomethylated genes.
69. Simpson, N. et al. Expansion of circulating T cells
resembling follicular helper T cells is a fixed phenotype
that identifies a subset of severe systemic lupus
erythematosus. Arthritis Rheum. 62, 234–244
(2010).
70. McKinney, E. F. et al. A CD8+ T cell transcription
signature predicts prognosis in autoimmune disease.
Nat. Med. 16, 586–591 (2010).
71. Xing, Q. et al. Elevated Th17 cells are accompanied
by FoxP3+ Treg cells decrease in patients with lupus
nephritis. Rheumatol. Int. 32, 949–958 (2012).
72. Lieberman, L. A. & Tsokos, G. C. The IL‑2 defect
in systemic lupus erythematosus disease has an
expansive effect on host immunity. J. Biomed.
Biotechnol. 2010, 740619 (2010).
73. Kil, L. P. et al. Btk levels set the threshold for B‑cell
activation and negative selection of autoreactive
B cells in mice. Blood 119, 3744–3756 (2012).
74. Mackay, M. et al. Selective dysregulation of the FcγIIB
receptor on memory B cells in SLE. J. Exp. Med. 203,
2157–2164 (2006).
75. Avalos, A. M. et al. Differential cytokine production
and bystander activation of autoreactive B cells in
response to CpG‑A and CpG‑B oligonucleotides.
J. Immunol. 183, 6262–6268 (2009).
76. Hiepe, F. et al. Long-lived autoreactive plasma cells
drive persistent autoimmune inflammation. Nat. Rev.
Rheumatol. 7, 170–178 (2011).
The inappropriate production of autoantibodies is
key to many autoimmune diseases including SLE.
Although current therapies can deplete the number
of B cells, long-lived plasma cells are refractory to
this treatment, can propagate autoimmunity and
are an important future therapeutic target.
77. Jacobi, A. M. et al. HLA-DRhigh/CD27high
plasmablasts indicate active disease in patients with
©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER
systemic lupus erythematosus. Ann. Rheum. Dis. 69,
305–308 (2010).
78. Zhu, H. et al. Autoantigen microarray for high-
throughput autoantibody profiling in systemic lupus
erythematosus. Genomics Proteomics Bioinformatics
13, 210–218 (2015).
79. Chen, Y. et al. Regulation of dendritic cells and
macrophages by an anti-apoptotic cell natural
antibody that suppresses TLR responses and inhibits
inflammatory arthritis. J. Immunol. 183, 1346–1359
(2009).
80. Liu, S. et al. Ongoing immunoglobulin class switch
DNA recombination in lupus B cells: analysis of switch
regulatory regions. Autoimmunity 37, 1431–1443
(2004).
81. DeGiorgio, L. A. et al. A subset of lupus anti-DNA
antibodies cross-reacts with the NR2 glutamate
receptor in systemic lupus erythematosus. Nat. Med.
7, 1189–1193 (2001).
82. Podolska, M. J. et al. Inflammatory etiopathogenesis
of systemic lupus erythematosus: an update.
J. Inflamm. Res. 8, 1161–1171 (2015).
83. Golbus, J. & McCune, W. J. Lupus nephritis.
Classification, prognosis, immunopathogenesis, and
treatment. Rheum. Dis. Clin. North Am. 20, 213–242
(1994).
84. Clynes, R., Dumitru, C. & Ravetch, J. V. Uncoupling
of immune complex formation and kidney damage
in autoimmune glomerulonephritis. Science 279,
1052–1054 (1998).
85. Knight, J. S. & Kaplan, M. J. Lupus neutrophils: ‘NET’
gain in understanding lupus pathogenesis. Curr. Opin.
Rheumatol. 24, 441–450 (2012).
86. Bethunaickan, R. et al. A unique hybrid renal
mononuclear phagocyte activation phenotype in
murine systemic lupus erythematosus nephritis.
J. Immunol. 186, 4994–5003 (2011).
87. Hsieh, C. et al. Predicting outcomes of lupus nephritis
with tubulointerstitial inflammation and scarring.
Arthritis Care Res. (Hoboken) 63, 5865–5874 (2011).
88. Deng, G. M. & Tsokos, G. C. Pathogenesis and
targeted treatment of skin injury in SLE. Nat. Rev.
Rheumatol. 11, 663–669 (2015).
89. Kaplan, M. J. Premature vascular damage in systemic
lupus erythematosus. Autoimmunity 42, 580–586
(2009).
90. McMahon, M. et al. Dysfunctional proinflammatory
high-density lipoproteins confer increased risk
of atherosclerosis in women with systemic lupus
erythematosus. Arthritis Rheum. 60, 2428–2437
(2009).
91. Lewis, M. J. et al. Improved monitoring of clinical
response in systemic lupus erythematosus by
longitudinal trend in soluble vascular cell adhesion
molecule‑1. Arthritis Res. Ther. 18, 5 (2016).
92. Gluhovschi, C. et al. What is the significance of
HLA‑DR antigen expression in the extraglomerular
mesangium in glomerulonephritis? Hum. Immunol.
73, 1098–1101 (2012).
93. Achtman, J. C. & Werth, V. P. Pathophysiology of
cutaneous lupus erythematosus. Arthritis Res. Ther.
17, 182 (2015).
94. Liao, R. et al. Tacrolimus protects podocytes from
injury in lupus nephritis partly by stabilizing the
cytoskeleton and inhibiting podocyte apoptosis.
PLoS ONE 10, e0132724 (2015).
95. Arnold, W. J. (ed.) American Rheumatism Association
Glossary Committee: Dictionary of the Rheumatic
Diseases. Vol I: Signs and Symptoms (American
College of Rheumatology, 1982).
96. Tan, E. M. et al. The 1982 revised criteria for the
classification of systemic lupus erythematosus.
Arthritis Rheum. 25, 1271–1277 (1982).
97. Hochberg, M. C. Updating the American College of
Rheumatology revised criteria for the classification
of systemic lupus erythematosus. Arthritis Rheum. 40,
1725 (1997).
98. Petri, M. et al. Derivation and validation of the
Systemic Lupus International Collaborating Clinics
classification criteria for systemic lupus erythematosus.
Arthritis Rheum. 64, 2677–2686 (2012).
99. Aggarwal, R. et al. Distinctions between diagnostic
and classification criteria? Arthritis Care Res.
(Hoboken) 67, 891–897 (2015).
100. Gladman, D. D., Ibanez, D. & Urowitz, M. B. Systemic
Lupus Erythematosus Disease Activity Index 2000.
J. Rheumatol. 29, 288–291 (2002).
101. Urowitz, M. B. et al. American College of
Rheumatology criteria at inception, and accrual over
5 years in the SLICC inception cohort. J. Rheumatol.
41, 875–880 (2014).
PRIMER
102. Ines, L. et al. Classification of systemic lupus
erythematosus: Systemic Lupus International
Collaborating Clinics Versus American College of
Rheumatology Criteria. A comparative study of 2,055
patients from a real-life, international systemic lupus
erythematosus cohort. Arthritis Care Res. (Hoboken)
67, 1180–1185 (2015).
103. Amezcua-Guerra, L. M., Higuera‑Ortiz, V.,
Arteaga‑García, U., Gallegos-Nava, S. & Hübbe-Tena, C.
Performance of the 2012 Systemic Lupus International
Collaborating Clinics and the 1997 American College of
Rheumatology classification criteria for systemic lupus
erythematosus in a real-life scenario. Arthritis Care Res.
(Hoboken) 67, 437–441 (2015).
104. Touma, Z., Gladman, D. D. & Urowitz, M. B. in Dubois
Lupus Erythematosus and Related Syndromes
(eds Wallace, D. J. & Hahn, B. H.) 563–581 (2013).
105. Abu-Shakra, M. et al. Mortality studies in systemic
lupus erythematosus. Results from a single center. II.
Predictor variables for mortality. J. Rheumatol. 22,
1265–1270 (1995).
106. Steiman, A. J. et al. Prolonged clinical remission
in patients with systemic lupus erythematosus.
J. Rheumatol. 41, 1808–1816 (2014).
107. Steiman, A. J. et al. Prolonged serologically active
clinically quiescent systemic lupus erythematosus:
frequency and outcome. J. Rheumatol. 37,
1822–1827 (2010).
108. Franklyn, K. et al. Definition and initial validation
of a Lupus Low Disease Activity State (LLDAS).
Ann. Rheum. Dis. http://dx.doi.org/10.1136/
annrheumdis-2015-207726 (2015).
109. Gladman, D. et al. The development and initial
validation of the Systemic Lupus International
Collaborating Clinics/American College of
Rheumatology damage index for systemic lupus
erythematosus. Arthritis Rheum. 39, 363–369 (1996).
110. Gladman, D. D. et al. The reliability of the Systemic
Lupus International Collaborating Clinics/American
College of Rheumatology Damage Index in patients
with systemic lupus erythematosus. Arthritis Rheum.
40, 809–813 (1997).
111. Rahman, P. et al. Early damage as measured by the
SLICC/ACR damage index is a predictor of mortality in
systemic lupus erythematosus. Lupus 10, 93–96
(2001).
112. Bruce, I. N. et al. Factors associated with damage
accrual in patients with systemic lupus erythematosus:
results from the Systemic Lupus International
Collaborating Clinics (SLICC) inception cohort.
Ann. Rheum. Dis. 74, 1706–1713 (2015).
This is a multinational study of 1,722 patients with
SLE that found that patients with tissue damage
are at higher risk of further damage accrual, earlier
mortality and worse physical functioning.
The identification of these patients represents
a key strategy in the future and may be predicted
by use of the SDI.
113. Gladman, D. D. et al. Recommendations for frequency
of visits to monitor systemic lupus erythematosus in
asymptomatic patients: data from an observational
cohort study. J. Rheumatol. 40, 630–633 (2013).
114. Mosca, L. et al. Effectiveness-based guidelines for
the prevention of cardiovascular disease in women
— 2011 update: a guideline from the American Heart
Association. J. Am. Coll. Cardiol. 57, 1404–1423
(2011).
115. Urowitz, M. B., Ibanez, D. & Gladman, D. D.
Atherosclerotic vascular events in a single large lupus
cohort: prevalence and risk factors. J. Rheumatol. 34,
70–75 (2007).
116. Tunnicliffe, D. J. et al. Diagnosis, monitoring
and treatment of systemic lupus erythematosus:
a systematic review of clinical practice guidelines.
Arthritis Care Res. (Hoboken) 67, 1440–1453 (2015).
Although management guidelines for SLE have
been published by several key groups, this
systematic analysis suggests that there are
substantial disparities between guidelines and
the need for more international consensus in the
management of patients with SLE. There is a
need for understudied areas of SLE to be better
represented in future guidelines.
117. Mosca, M. et al. European League Against
Rheumatism recommendations for monitoring
patients with systemic lupus erythematosus in clinical
practice and in observational studies. Ann. Rheum.
Dis. 69, 1269–1274 (2010).
118. Bultink, I. E. Osteoporosis and fractures in systemic
lupus erythematosus. Arthritis Care Res. (Hoboken)
64, 72–78 (2012).
20 | 2016 | VOLUME 2 www.nature.com/nrdp
119. Jeltsch-David, H. & Muller, S. Neuropsychiatric
systemic lupus erythematosus: pathogenesis and
biomarkers. Nat. Rev. Neurol. 10, 579–596 (2014).
120. Ibanez, D. et al. Optimal frequency of visits for patients
with systemic lupus erythematosus to measure disease
activity over time. J. Rheumatol. 38, 60–63 (2011).
121. Pego-Reigosa, J. M. et al. Efficacy and safety of
nonbiologic immunosuppressants in the treatment of
nonrenal systemic lupus erythematosus: a systematic
review. Arthritis Care Res. (Hoboken) 65, 1775–1785
(2013).
122. Alarcon, G. S. et al. Effect of hydroxychloroquine on the
survival of patients with systemic lupus erythematosus:
data from LUMINA, a multiethnic US cohort
(LUMINA L). Ann. Rheum. Dis. 66, 1168–1172 (2007).
123. Tsakonas, E. et al. A long-term study of
hydroxychloroquine withdrawal on exacerbations
in systemic lupus erythematosus. The Canadian
Hydroxychloroquine Study Group. Lupus 7,
1180–1185 (1998).
124. Chen, Y.‑M. et al. Hydroxychloroquine reduces risk of
incident diabetes mellitus in lupus patients in a dose-
dependent manner: a population based cohort study.
Rheumatology (Oxford) 54, 1244–1249 (2015).
125. van Vollenhoven, R. F. et al. Belimumab in the
treatment of systemic lupus erythematosus: high
disease activity predictors of response. Ann. Rheum.
Dis. 71, 1343–1349 (2012).
126. Wallace, D. J. et al. Safety profile of belimumab:
pooled data from placebo-controlled phase 2 and 3
studies in patients with systemic lupus erythematosus.
Lupus 22, 1144–1154 (2013).
127. Petri, M. A. et al. Effects of prasterone on disease
activity and symptoms in women with active systemic
lupus erythematosus. Arthritis Rheum. 50,
2858–2568 (2004).
128.van Vollenhoven, R. F. & McGuire, J. L. Estrogen,
progesterone, and testosterone: can they be used
to treat autoimmune diseases? Cleve. Clin. J. Med. 61,
2276–2284 (1994).
129. Naafs, B. et al. Thalidomide treatment of subacute
cutaneous lupus erythematosus. Br. J. Dermatol. 107,
83–86 (1982).
130. Wolfe, F. et al. Fibromyalgia, systemic lupus
erythematosus (SLE), and evaluation of SLE activity.
J. Rheumatol. 36, 82–88 (2009).
131. Appenzeller, S., Pallone, A. T., Natalin, R. A.
& Costallat, L. T. Prevalence of thyroid dysfunction
in systemic lupus erythematosus. J. Clin. Rheumatol.
15, 117–119 (2009).
132. Gladman, D. et al. Accrual of organ damage over time
in patients with systemic lupus erythematosus.
J. Rheumatol. 30, 1955–1959 (2003).
133. Thamer, M. et al. Prednisone, lupus activity
and permanent organ damage. J. Rheumatol. 36,
560–564 (2009).
134. Chambers, S. et al. Damage and mortality in a group
of British patients with systemic lupus erythematosus
followed up for over 10 years. Rheumatology (Oxford)
48, 673–675 (2009).
135. Fischer-Betz, R. et al. Renal outcome in patients with
lupus nephritis using a steroid-free regimen of monthly
intravenous cyclophosphamide: a prospective
observational study. J. Rheumatol. 39, 2211–2217
(2012).
136. Zeher, M. et al. Efficacy and safety of enteric-coated
mycophenolate sodium in combination with two
glucocorticoid regimens for the treatment of active
lupus nephritis. Lupus 20, 1484–1493 (2011).
137. Condon, M. B. et al. Prospective observational
single‑centre cohort study to evaluate the effectiveness
of treating lupus nephritis with rituximab and
mycophenolate mofetil but no oral steroids.
Ann. Rheum. Dis. 72, 1280–1286 (2013).
Although evidence from case series suggested that
B cell depletion with rituximab had benefits in SLE
nephritis, the LUNAR and EXPLORER trials
did not meet end points. This open-label study
demonstrates that rituximab and low-dose
glucocorticoids in class IV SLE nephritis can
be effective treatments.
138. Tak, M. Treatment of severe lupus nephritis: the new
horizon. Nat. Rev. Nephrol. 11, 46–61 (2015).
Historically, cyclophosphamide with its attendant
adverse effects had been the mainstay of
treatment for patients with SLE nephritis. This
review demonstrates the progression to increased
use of mycophenolate mofetil as induction therapy,
owing to its efficacy at inducing remission
compared with lupus nephritis, with a better
safety profile than cyclophosphamide.
©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
139. Houssiau, F. A. et al. Immunosuppressive therapy
in lupus nephritis: the Euro-Lupus Nephritis Trial,
a randomized trial of low-dose versus high-dose
intravenous cyclophosphamide. Arthritis Rheum. 46,
2121–2131 (2002).
140. Houssiau, F. A. et al. The 10‑year follow‑up data
of the Euro-Lupus Nephritis Trial comparing low-dose
and high-dose intravenous cyclophosphamide.
Ann. Rheum. Dis. 69, 61–64 (2010).
141. Gunnarsson, I. & Jonsdottir, T. Rituximab treatment
in lupus nephritis — where do we stand? Lupus 22,
381–389 (2013).
142. Rovin, B. H. et al. Efficacy and safety of rituximab in
patients with active proliferative lupus nephritis:
the lupus nephritis assessment with rituximab study.
Arthritis Rheum. 64, 1215–1226 (2012).
143. van Vollenhoven, R. F. Rituximab — shadow, illusion
or light? Autoimmun. Rev. 11, 563–567 (2012).
144. US National Library of Medicine. RING — rituximab
for lupus nephritis with remission as a goal (RING).
ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/
NCT01673295 (2012).
145. Dooley, M. A. et al. Mycophenolate versus
azathioprine as maintenance therapy for lupus
nephritis. N. Engl. J. Med. 365, 1886–1895 (2011).
146. Houssiau, F. A. et al. Azathioprine versus
mycophenolate mofetil for long-term
immunosuppression in lupus nephritis: results from
the MAINTAIN Nephritis trial. Ann. Rheum. Dis. 69,
2083–2089 (2010).
147. Pons-Estel, G. et al. Therapeutic plasma exchange for
the management of refractory systemic autoimmune
diseases: report of 31 cases and review of the
literature. Autoimmun. Rev. 10, 679–684 (2011).
148. Schmeding, A. & Schneider, M. Fatigue, health-related
quality of life and other patient-reported outcomes
in systemic lupus erythematosus. Best Prac. Res. Clin.
Rheumatol. 27, 363–375 (2013).
149. Yelin, E. et al. Work dynamics among persons with
systemic lupus erythematosus. Arthritis Rheum. 57,
356–363 (2007).
150. Gordon, C. et al. The substantial burden of systemic
lupus erythematosus on the productivity and careers
of patients: a European patient-driven online survey.
Rheumatology (Oxford) 52, 2292–2301 (2013).
151. Yazdany, J. Health-related quality of life measurement
in adult systemic lupus erythematosus: Lupus Quality
of Life (LupusQoL), Systemic Lupus Erythematosus-
Specific Quality of Life Questionnaire (SLEQOL),
and Systemic Lupus Erythematosus Quality of Life
Questionnaire (L-QoL). Arthritis Care Res. (Hoboken)
63, S2413–S2419 (2011).
152. Gladman, D. et al. Systemic Lupus International
Collaborating Clinics conference on assessment of
lupus flare and quality of life measures in SLE.
Systemic Lupus International Collaborating Clinics
Group. J. Rheumatol 23, 1953–1955 (1996).
153. Dua, A. B. et al. Top 10 recent developments in health-
related quality of life in patients with systemic lupus
erythematosus. Curr. Rheumatol. Rep. 15, 380 (2013).
154. Ahn, G. E. & Ramsey-Goldman, R. Fatigue in systemic
lupus erythematosus. Int. J. Clin. Rheumtol. 7,
217–227 (2012).
This paper is an overview of the factors that are
important in SLE fatigue. Although obesity, physical
activity levels, depression, anxiety and vitamin D
levels are important, the relationship to disease
activity levels is much less clear.
155. Ruiz-Irastorza, G., Gordo, S., Olivares, N.,
Egurbide, M.‑V. & Aguirre, C. Changes in vitamin D
levels in patients with systemic lupus erythematosus:
effects on fatigue, disease activity, and damage.
Arthritis Care Res. (Hoboken) 62, 1160–1165 (2010).
156. Furie, R. et al. Clinical, laboratory and health-related
quality of life correlates of Systemic Lupus
Erythematosus Responder Index response:
a post hoc analysis of the phase 3 belimumab trials.
Lupus Sci. Med. 1, e000031 (2014).
157. Hanly, J. G. et al. Mood disorders in systemic lupus
erythematosus: results from an international, inception
cohort study. Arthritis Rheum. 67, 1837–1847 (2015).
158. Ruiz-Arruza, I. et al. Glucocorticoids and irreversible
damage in patients with systemic lupus
erythematosus. Rheumatology (Oxford) 53,
1470–1476 (2014).
Using an observational cohort of 230 patients with
SLE at inception with a 5‑year follow-up and SLICC
as a measure of tissue damage, 37% of patients
had accrued damage. Doses of >7.5 mg daily of
glucocorticoids were associated with higher levels
of damage attributable to the drug.

159. Scofield, L., Reinlib, L., Alarcón, G. S. & Cooper, G. S.
Employment and disability issues in systemic lupus
erythematosus: a review. Arthritis Care Res. (Hoboken)
59, 1475–1479 (2008).
160. Arbuckle, M. R. et al. Development of autoantibodies
before the clinical onset of systemic lupus
erythematosus. N. Engl. J. Med. 349, 1526–1533
(2003).
161. James, J. A. et al. Hydroxychloroquine sulfate
treatment is associated with later onset of systemic
lupus erythematosus. Lupus 16, 1401–1409 (2007).
162. Doria, A. et al. Long-term prognosis and causes of
death in systemic lupus erythematosus. Am. J. Med.
119, 700–706 (2006).
163. Abd-Elkareem, M. I., Al Tamimy, H. M., Khamis, O. A.,
Abdellatif, S. S. & Hussein, M. R. Increased urinary
levels of the leukocyte adhesion molecules ICAM‑1
and VCAM‑1 in human lupus nephritis with advanced
renal histological changes: preliminary findings.
Clin. Exp. Nephrol. 14, 548–557 (2010).
164. Xuejing, Z. et al. Urinary TWEAK level as a marker
of lupus nephritis activity in 46 cases. J. Biomed.
Biotechnol. 2012, 359647 (2012).
165. Lapteva, L. et al. Anti‑N‑methyl-d‑aspartate receptor
antibodies, cognitive dysfunction, and depression in
systemic lupus erythematosus. Arthritis Rheum. 54,
2505–2514 (2006).
166. Kowal, C. et al. Human lupus autoantibodies against
NMDA receptors mediate cognitive impairment.
Proc. Natl Acad. Sci. USA 103, 19854–19859
(2006).
167. Urowitz, M. B. et al. The bimodal mortality pattern
of systemic lupus erythematosus. Am. J. Med. 60,
19221–19225 (1976)
168. Magder, L. S. & Petri, M. Incidence of and risk factors
for adverse cardiovascular events among patients with
systemic lupus erythematosus. Am. J. Epidemiol. 176,
708–719 (2012).
169. Esdaile, J. M. et al. Traditional Framingham risk
factors fail to fully account for accelerated
atherosclerosis in systemic lupus erythematosus.
Arthritis Rheum. 44, 2331–2337 (2001).
170. Bertsias, G. et al. EULAR recommendations for
the management of systemic lupus erythematosus.
Report of a Task Force of the EULAR Standing
Committee for International Clinical Studies Including
Therapeutics. Ann. Rheum. Dis. 67, 195–120
(2008).
171. Lai, C. H. et al. Outcomes of percutaneous coronary
intervention in patients with rheumatoid arthritis and
systemic lupus erythematosus: an 11‑year nationwide
cohort study. Ann. Rheum. Dis. http://dx.doi.org/
10.1136/annrheumdis-2015-207719 (2015).
172. Myasoedova, E. et al. Lipid paradox in rheumatoid
arthritis: the impact of serum lipid measures and
systemic inflammation on the risk of cardiovascular
disease. Ann. Rheum. Dis. 70, 482–487 (2011).
173. van Vollenhoven, R. F. et al. Treat‑to‑target in systemic
lupus erythematosus: recommendations from
an international task force. Ann. Rheum. Dis. 73,
958–967 (2014).
174. Drenkard, C. et al. Remission of systematic lupus
erythematosus. Medicine 75, 88–98 (1996).
175. Nossent, J. et al. Disease activity and damage
accrual during the early disease course in a
multinational inception cohort of patients with
systemic lupus erythematosus. Lupus 19, 949–956
(2010).
176. Zen, M. et al. Prolonged remission in Caucasian
patients with SLE: prevalence and outcomes.
Ann. Rheum. Dis. 74, 2117–2122 (2015).
177. Urowitz, M. B. et al. Prolonged remission in systemic
lupus erythematosus. J. Rheumatol 8, 1467–1472
(2005).
178. Mosca, M. et al. Treat‑to‑target in systemic lupus
erythematosus: where are we today? Clin. Exp.
Rheum. 30, S112–S115 (2012).
179. US FDA. Guidance for Industry. Systemic Lupus
Erythematosus — Developing Medical Products for
Treatment (FDA, 2010)
180. Wallace, D. J. et al. Efficacy and safety of epratuzumab
in patients with moderate/severe active systemic lupus
erythematosus: results from EMBLEM, a phase IIb,
randomised, double-blind, placebo-controlled,
multicentre study. Ann. Rheum. Dis. 73, 183–190
(2014).
181. Clowse, M. E. B. et al. Efficacy safety epratuzumab
patients with moderate-to‑severe system. lupus
erythematosus: results from two phase 3 randomized,
placebo-controlled trials. Arthritis Rheumatol. Abstr.
67 (Suppl. 10), 4L (2015).
NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 21
182. US National Library of Medicine. Rituximab and
belimumab for lupus nephritis. ClinicalTrials.gov
https://clinicaltrials.gov/ct2/show/
NCT02260934?term=NCT02260934&rank=1
(2014).
183. Koenen, H. J. et al. A novel bispecific antihuman
CD40/CD86 fusion protein with T‑cell tolerizing
potential. Transplantation 78, 1429–1438 (2004).
184. Kyttaris, V. C., Juang, Y.‑T. & Tsokos, G. C. Gene
therapy in systemic lupus erythematosus. Lupus 13,
353–358 (2004).
185. Collins, E. & Gilkeson, G. Hematopoetic and
mesenchymal stem cell transplantation in the
treatment of refractory systemic lupus erythematosus
— where are we now? Clin. Immunol. 148, 328–334
(2013).
This paper is an overview of the challenges facing
stem cell transplantation for SLE. Only refractory
patients with severe disease have been offered
stem cell procedures and this has meant that
mortality from the procedure remains high.
The use of different conditioning regimes and
non-myeloablative mesenchymal stem cells may
be an important factor in promoting the success
of these regimes in future.
186. Bombardier, C., Gladman, D. D., Urowitz, M. B.,
Caron, D. & Chang, C. H. Derivation of the SLEDAI.
A disease activity index for lupus patients.
The Committee on Prognosis Studies in SLE.
Arthritis Rheum. 35, 630–640 (1992).
187. Touma, Z. et al. SLEDAI‑2K 10 days versus SLEDAI‑2K
30 days in a longitudinal evaluation. Lupus 20, 67–70
(2011).
188. Petri, M. et al. Combined oral contraceptives in
women with systemic lupus erythematosus. N. Engl.
J. Med. 353, 2550–2558 (2005).
189. Symmons, D. P. et al. Development and assessment
of a computerized index of clinical disease activity in
systemic lupus erythematosus. Members of the British
Isles Lupus Assessment Group (BILAG). Q. J. Med. 69,
927–937 (1988).
190. Isenberg, D. A. et al. BILAG 2004. Development and
initial validation of an updated version of the British
Isles Lupus Assessment Group’s disease activity index
for patients with systemic lupus erythematosus.
Rheumatology (Oxford) 44, 902–906 (2005).
191. Touma, Z., Gladman, D. D., Ibañez, D. & Urowitz, M.B.
Development and initial validation of the Systemic
Lupus Erythematosus Disease Activity Index 2000
responder index 50. J. Rheumatol. 38, 275–284
(2011).
192. Furie, R. A. et al. Novel evidence-based systemic lupus
erythematosus responder index. Arthritis Rheum. 61,
1143–1151 (2009).
193. Ibanez, D., Gladman, D. D. & Urowitz, M. Summarizing
disease features over time: II. Variability measures
of SLEDAI‑2K. J. Rheumatol. 34, 336–340 (2007).
194. Li, Z.‑G., Mu, R., Dai, Z.‑P. & Gao, X.‑M. T‑cell
vaccination in systemic lupus erythematosus with
autologous activated T‑cells. Lupus 14, 884–889
(2005).
195. Ponticelli, C. & Moroni, G. Monoclonal antibodies for
systemic lupus erythematosus (SLE). Pharmaceuticals
3, 300–322 (2010).
196. Isenberg, D. et al. Efficacy and safety of atacicept
for prevention of flares in patients with moderate-
to‑severe systemic lupus erythematosus (SLE):
52‑week data (APRIL-SLE randomised trial).
Ann. Rheum. Dis. 74, 2006–2015 (2015).
197. Furie, R. A. et al. A phase 2, randomised, placebo-
controlled clinical trial of blisibimod, an inhibitor of
B cell activating factor, in patients with moderate-
to‑severe systemic lupus erythematosus, the PEARL‑SC
study. Ann. Rheum. Dis. 74, 1667–1675 (2015).
198. Isenberg, D. et al. Efficacy and safety of tabalumab
in patients with systemic lupus erythematosus (SLE):
results from 2 phase 3, 52‑week, multicenter,
randomized, placebo-controlled trials. 74, 141 (2015).
199. Alarcon-Segovia, D. et al. LJP 394 for the prevention
of renal flare in patients with systemic lupus
erythematosus. Arthritis Rheum. 48, 442–454
(2003).
200. Aringer, M. et al. Adverse events and efficacy of
anti‑TNF-α blockade with infliximab in patients with
systemic lupus erythematosus: long term follow up
of 13 patients. Rheumatology (Oxford) 48,
1451–1454 (2009).
201. Ostendorf, B. et al. Preliminary results of safety
and efficacy of the interleukin‑1 receptor antagonist
anakinra in patients with severe lupus arthritis.
Ann. Rheum. Dis. 64, 630–633 (2005).
©
2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER
202. Wallace, D. J. et al. Improvement of disease activity
and reduction of severe flares following subcutaneous
administration of IL‑6 monoclonal antibody (mAb) in
subjects with active generalized systemic lupus
erythematosus (SLE). ACR http://acrabstracts.org/
abstract/improvement-of-disease-activity-and-
reduction-of-severe-flares-following-subcutaneous-
administration-of-an-il-6-monoclonal-antibody-mab-
in-subjects-with-active-generalized-systemic-lupus-
erythematos/ (2014).
203. Llorente, L. et al. Clinical and biologic effects
of anti‑interleukin‑10 monoclonal antibody
administration in systemic lupus erythematosus.
Arthritis Rheum. 43, 1790–1800 (2000).
204. Khamashta, M. et al. Safety efficacy sifalimumab,
anti IFN-α monoclonal antibody, phase 2b study
moderate severe system. lupus erythematosus (SLE).
Arthritis Rheum. Abstr. 66, S312 (2014).
205. Furie, R. et al. Anifrolumab, an anti-interferon α
receptor monoclonal antibody, in moderate
to severe systemic lupus erythematosus (SLE).
Arthritis Rheumatol. Abstr. 67 (Suppl. 10), 3223
(2015).
206. Omdal, R. et al. Fatigue in patients with systemic
lupus erythematosus: the psychosocial aspects.
J. Rheumatol. 30, 283–287 (2003).
207. Ad hoc Committee on Systemic Lupus Erythematosus
Response Criteria for Fatigue. Measurement of fatigue
in systemic lupus erythematosus: a systematic review.
Arthritis Rheum. 57, 1348–1357 (2007).
208. Hanly, J. G., Omisade, A., Su, L., Farewell, V.
& Fisk, J. D. ANAM: automated psychological
assessment metrics assessment of cognitive function
in systemic lupus erythematosus, rheumatoid arthritis,
and multiple sclerosis by computerized
neuropsychological tests. Arthritis Rheum. 62,
1478–1486 (2010).
209. Panopalis, P. et al. The systemic lupus erythematosus
tri-nation study: longitudinal changes in physical and
mental well-being. Rheumatology (Oxford) 44,
751–755 (2005).
210. Fortin, P. R. et al. Impact of disease activity and
cumulative damage on the health of lupus patients.
Lupus 7, 101–107 (1998).
211. Alarcon, G. S. et al. Systemic lupus erythematosus in
a multiethnic lupus cohort (LUMINA). XVII. Predictors
of self- reported health-related quality of life early in
the disease course. Arthritis Rheum. 51, 465–474
(2004).
212. Fernandez, M. et al. Using the Short Form 6D,
as an overall measure of health, to predict damage
accrual and mortality in patients with systemic lupus
erythematosus: XLVII, results from a multiethnic
US Cohort. Arthritis Rheum. 57, 986–992 (2007).
213. Bertoli, A. M. et al. Systemic lupus erythematosus in a
multiethnic US cohort LUMINA (XLI): factors predictive
of self-reported work disability. Ann. Rheum. Dis. 66,
12–17 (2007).
214. Baker, K. & Pope, J. Employment and work disability
in systemic lupus erythematosus: a systematic review.
Rheumatology (Oxford) 48, 281–284 (2009).
215. Panopalis, P., Petri, M., Manzi, S. & the Tri-Nation
Study Group. The Systemic Lupus Erythematosus
Tri‑Nation Study: cumulative indirect costs.
Arthritis Rheum. 57, 64–70 (2007).
216. Clarke, A. E., Urowitz, M. B., Monga, N. & Hanly, J. G.
Costs associated with severe and nonsevere systemic
lupus erythematosus in Canada. Arthritis Care Res.
(Hoboken) 67, 431–436 (2015).
Author contributions
Introduction (A.K. and G.H.); Epidemiology (C.G.);
Mechanisms/pathophysiology (M.K.C.); Diagnosis,
screening and prevention (Z.T. and M.B.U.); Management
(R.v.V.); Quality of life (G.R.-I.); Outlook (A.K.); Overview of
Primer (A.K.).
Competing interests
A.K. has received honoraria for speaking as well as research
grants from Janssen, Celgene, Pfizer and Wyeth. C.G. has
received consulting fees and/or honoraria from Bristol-Myers
Squibb (BMS), GlaxoSmithKline (GSK), Lilly, Merck Serono,
Parexel and UCB and grant support from UCB. R.v.V. has
received research support or grants from AbbVie, Amgen,
BMS, GSK, Pfizer, Roche and UCB and consulting fees or
honoraria from AbbVie, Biotest, BMS, Celgene, Crescendo,
GSK, Janssen, Lilly, Merck, Novartis, Pfizer, Roche, UCB and
Vertex. M.K.C. has received consulting fees or research
support from AstraZeneca, BMS, GSK, Lilly, MedImmune,
Novartis, Novo Nordisk and Pfizer. All other authors declare
no competing interests.