Lupus

PRIMER

Systemic lupus erythematosus

Arvind Kaul 1 , Caroline Gordon 2 , Mary K. Crow 3 , Zahi Touma 4 , Murray B. Urowitz 4 ,

Ronald van Vollenhoven 5 , Guillermo Ruiz-Irastorza 6 and Graham Hughes 7

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 typically

affects women between puberty and menopause.

Defects can occur in many parts of the immune cascade

resulting in a striking heterogeneity of clinical presentations.

Delay in diagnosis is associated with increased

damage to vital organ systems 1 .

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 SLE 2 . Some of the strongest

genetic links to SLE are the rare complement component

C1Q and C4 single-gene defects 3,4 . In most patients, SLE

is a quantitative trait with several genes contributing to

the risk of developing the disease; genome-wide association

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 endocrine

factors are important. Indeed, when patients with

SLE are given oestrogen and progesterone hormonereplacement

therapy, their risk of SLE flare is 1.34 times

that of women given placebo 6 . In addition, low levels

of dehydroepiandrosterone (DHEA), a steroid intermediate

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 disease 7 .

The complexity of SLE is indicated by diverse clinical

features (including arthritis and neurological, renal,

cutaneous and gastrointestinal manifestations; FIG. 1)

and laboratory abnormalities (including haematological

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 associated

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

©2016 Mac mill an Publishers Li mited. All ri ghts reserved.

PRIMER

Author addresses

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 thrombosis 8 . 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 improvement

in survival reached a plateau in the 1980s and

1990s despite improvements in diagnosis and treatment.

This may be owing to increasing levels of SLEassociated

damage accrual and morbidity that occur

with increasing lifespan 10 .

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 measures 12 .

This Primer explores the nature of SLE and its causes

and effects on patient well-being in more detail. In addition,

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

consider ably between countries 13 . 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 populations 14 . Annual incidence

rates in the United States range from 2 to 7.6 per 100,000

and prevalence varies even more widely from 19 to

159 per 100,000 depending on the defin ition of SLE

used, methods of case ascertainment, age standardization

and the racial and ethnic background of the

population 15,16 . Similarly, figures for Europe show

considerable vari ation with annual incidence rates

between 1 and 4.9 per 100,000 and prevalence 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 menopause

14 . 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 studies 19,20 . SLE is more common in

certain racial and ethnic groups 15,20 (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 disease)

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 origin 20,22 , Native Americans, (including

Alaska Natives) 23 and Indigenous Australians 24,25 .

Although populations of people with Chinese backgrounds

have been reported to have an increased prevalence

of SLE 26 , lower regional rates have been reported

from Korea 27,28 .

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 metaanalysis

29 . People of African, Chinese and Hispanic

origin with SLE have an increased frequency of SLEassociated

renal complications (that is, lupus nephritis)

— one of the strongest predictors of an increased

mortality risk 30,31 . 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

backgrounds 22,30,31 . Other explanations for the variability

in mortality risk between different populations are

different beliefs and perceptions about the condition as

well as the availability of and adherence to treatments 13 .

Furthermore, infection constitutes another important

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

inappro priate immune response to nucleic acidcontaining

cellular particles. However, the production

of anti bodies against these nucleic acids (antinuclear

antibodies (ANAs)) is fairly common in the general

popu lation and not all people who have ANAs develop

SLE, suggesting that other mechanisms must promote

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


PRIMER

Neurological complications (50%)

Constitutional symptoms

and fevers (70%)

Pericarditis

and effusion

(20%)

Raynaud

phenomenon

(20%)

the progression of autoimmunity into overt disease.

Key determinants of this progression include genetic

susceptibility factors that shape immune function, sex

and stochastic factors that affect responses to exogenous

or endogenous triggers. A remaining mystery is

the significance of those autoantibody specificities

that characterize patients with SLE (BOX 1), particularly

those that are most specific to SLE compared with

other autoimmune disorders: anti-Smith (Sm) antibodies,

which are directed against a component of the

spliceosome, and anti- double-stranded DNA (dsDNA)

antibodies. Experimental models of chronic virus infection,

such as lymphocytic chorio meningitis virus and

human immuno deficiency virus, suggest a framework

for understanding some aspects of the immunopathogenetics

of SLE, particularly with regards to the sustained

production of type I IFNs seen in many patients

with the disease 33 (BOX 2).

Cutaneous and mucosal

complications (70%)

Pleural effusion

(40%)

Renal

complications

(30%)

Gastrointestinal

complications (50%)

Haematological

complications

(50%)

Arthritis and

musculoskeletal

complications

(85%)

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.

Genetic factors

Low-frequency single-gene mutations with substantial

impact on SLE susceptibility have been described 34 .

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 debris 34 , with increased availability

of nucleic acid-containing cell products as a

consequence 35 . The ancestral major histocompatibility

complex (MHC) 8.1 haplotype associated with

SLE susceptibil ity 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,

anti bodies 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 restriction 36 . 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 susceptibil ity 37 . In addition to its role in clearance

of apoptotic cell debris, C1q might provide protection

from SLE by directing stimulatory immune

complexes to monocytes rather than IFNα‐producing

plasmacytoid dendritic cells 38 .

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 disease

and high levels of type I IFNs 39 . These mutations

and genetic associations support a role for stimulatory

cytoplasmic nucleic acids as triggers for immune system

activation in SLE 40 .

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 activation 41 .

Another set of SLE-associated gene variants contributes

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 autoantibodies

are produced, possibly as a result of MHC



PRIMER

restriction 36 , these SLE-associated variants encode for

proteins involved in cytokine signalling (for example,

signal transducer and activator of transcrip tion 4

(STAT4)) and in the efficiency of signalling downstream

of T cell and B cell surface antigen receptors

(for example, tyrosine-protein phosphatase

non- receptor type 22 (PTPN22), tyrosine-protein kinase

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 kallikreinencoding

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 oxidative damage 43 .

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 lymphocytes,

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 characterized

by a 47XXY genotype, is increased 14‐fold among

men with SLE compared with men without SLE, suggesting

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 activation 45 .

Environmental triggers

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 defective

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 SLE 46 . EBV might contribute to

innate immune system activation and B cell differentiation,

and could stimulate the production of autoantibodies

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, suggesting

that EBV infection could induce an auto immune

response 47 . The molecular basis of this apparent crossreactivity

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 mech anism

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 methylation 49 . 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

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

Denmark 17 1 NA NA 28 NA NA NA NA

United Kingdom 20 4.6 7.8 1.3 88 152 22 525* 124

American Indian Health Service 23 7.4 10.4 NA 178 271 54 NA NA

Taiwan 26 4.9 ‡ NA NA 98 ‡ NA NA NA NA

Korea 27,28 NA NA NA 19–22 ‡ NA NA NA NA

2.5 ‡ NA NA 27 ‡ NA NA NA NA

Australia 24,25 NA NA NA NA NA NA 74 § 19

NA NA NA 45 NA NA 93 NA

White

people

NA, not available; SLE, systemic lupus erythematosus. *The majority of the study population are black people of African-Caribbean

origin. ‡ Chinese origin. § Indigenous Australians.



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 cigarettes

smoked per year and the development of SLE 50 .

Smoking might provide an inflammatory stimulus to

epithelial or mononuclear cells in the lungs, promoting

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 responses 51 .

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 system

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 TLRindependent

nucleic acid sensors, leading to type I

IFN production and immune dysfunction in SLE 33,52 .

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, particularly

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

interactions 56 . Moreover, autoantibodies with specificity

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 SLE 57 . 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 antibodies 58 . 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 cyto plasmic

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 pathogenesis,

perhaps in other cells such as epithelial cells 60,61 .

Although plasmacytoid dendritic cells are the main

source of type I IFNs, other cell types might be involved

in amplifying IFN signalling. Microarray analyses

showed that an IFN gene expression signature in

peripheral blood cells was associated with the expression

of genes that are typically expressed in granulocytes

and neutrophil extracellular traps (NETs), suggesting a

potential role of these factors in innate immune system

activation 53 . NETS comprise a network of extracellular

fibres that contain DNA and pro-inflammatory proteins

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 dendritic

cells, serve as a source of relevant self-antigens

for presentation to T lymphocytes and mediate vascular

damage and thrombosis 62 .

Adaptive immune system activation

T cells. T cells are important contributors to SLE pathogenesis.

Deficiencies or alterations in T cell signalling,

in the production of cytokines, in proliferation and in

regulatory functions have been documented in patients

with SLE 63 . 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

differentiation 64 . T cells derived from patients with

SLE readily express CD40 ligand (CD40L) after activation

and maintain the expression of this important costimulatory

molecule longer than T cells derived from

healthy controls 65 , leading to augmented help for the

activation and differentiation of B cells. The molecular

basis of the altered T cell activation in patients

with SLE is complex. Altered expression of components

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

intra cellular calcium signalling and hyperpolarization

of mitochondria have been observed in the presence of

TCRγ compared with TCRζ, which can sensitize T cells

for necrosis 67 . Correction of this defect can normalize

T cell signalling 66 .



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 genes 68 . Epigenetic modifications

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 antigen

1 (LFA1) is the most likely factor responsible for

the produc tive interactions between macrophages and

T cells that result in increased T cell proliferation.

Generalized lymphocytopaenia is a typical

character istic of SLE, but the expansion of specific

T cell populations has been described. The population

of T follicular helper cells, which promote differentiation

of autoantibody-producing B cells, is expanded

in SLE 69 . As T follicular helper cells may be essential

for the differ entiation of pathogenetic autoantibodyproducing

B cells, they represent an important therapeutic

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 damage 70 . Regulatory T (T reg

) cells,

with the capacity to suppress immune responses, and

T helper 17 (T H

17) cells, which promote inflammation

by the production of IL‐17, have been intensively studied

in recent years. Some studies have shown a relative

depletion in the number of T reg

cells, increased numbers

of T H

17 cells and increased levels of IL‐17 in SLE 71 . The

functional consequences of these alterations in human

SLE are still not clear. Decreased production of IL‐2 is

a character istic 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 haplotype 37 . 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 recognition

that IL‐2 is important for the maintenance of

T reg

cells suggests another mechanism through which

impaired production of IL‐2 might contribute to

immune system activation and autoimmunity 72 .

B cells. B cell regulation is also impaired in SLE, contributing

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 differenti ation

factors (including BAFF and IL‐21) and activation

of TLRs all contribute to autoimmunity, but intrinsic

differences in threshold for the activation and signalling

of B cells in mouse lupus models have also been

described 73 . 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 antigenmediated

B cell activation 42 . 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 production

when engaged by nucleic acid-containing immune

complexes 74,75 . Long-lived plasma cells are maintained

by chemokines and stromal cell products in protective

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 association

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 autoantibodies

(BOX 1). Autoantibodies in SLE can be categorized

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 ribonucleoprotein

particles; β2‐glycoprotein 1 in association with

phospholipids; and cell membrane proteins, typically

those expressed on blood cells. Among those, antidsDNA

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 pathogenetic 78 .

The pathogenetic antibodies in SLE undergo

immuno globulin 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



PRIMER

representing an important point of altered immune

regu lation that contributes to SLE immunopathogenesis.

Some IgM natural antibodies react with apoptotic cells

and inhibit their activation through TLRs 79,80 . Arginines

in the complementarity-determining region 3 region of

anti-dsDNA antibodies are characteristic of SLE autoantibodies

and influence binding to their DNA target.

Some antibodies unexpectedly bind to two distinct

self-antigens. For example, some anti-dsDNA anti bodies

also bind to a peptide that is a feature of glutamate

receptors on central nervous system neurons 81 .

The role of SLE autoantibodies in the patho genesis

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

contrib ution of direct targeting of antibodies to antigens

deposited in situ 82 . In recent years, with the recognition

that nucleic acid-containing immune complexes can

directly induce cell signalling and new gene transcrip tion

after accessing endosomal TLRs 59 , an additional pathogenetic

role for autoantibodies as immune modulators

has been defined.

Mechanisms of target organ damage

Clinical disease is ultimately a reflection of tissue damage

mediated by the inflammatory consequences of

autoimmunity and immune system activation, along

with an exaggerated or aberrant repair response.

A trad itional 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 macrophages 83 .

However, deposition of autoantibodies or immune

complexes in a target organ is not sufficient for the

gener ation 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 various

disease stages have identified a monocyte population

that has undergone differentiation to mediate what is

apparently uncontrolled tissue repair, contributing to

sclerosis and organ dysfunction 86 . 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 important

for organ damage as those in the glomerulus. The

presence of B cells in the interstitium is associated with

increased risk of future renal failure 87 , 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 interactions

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 tissues 88 .

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 pathways

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 patho genetic 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 effector

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

contrib ute to SLE pathology. Altered structure and function

of venous and arterial blood vessels, seen as periarticular

(concentric ‘onion-skinning’) in the spleen, and

microangiopathy and associated microthrombi in the

kidneys and endothelial dysfunction have been associated

with premature atherosclerosis in SLE 89 . 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 damage 89 .

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 atherosclerosis 90 . These mechanisms are in

addition to the previously described role of complement



PRIMER

Table 2 | Selected drugs implicated in drug-induced SLE

Drug Indication Prevalence

of ANAs

(%)

Procainamide Anti-arrhythmic agent 75 15–20

Minocycline Broad-spectrum antibiotic 90 10–15

Hydralazine Vasodilator 15–45 5–10

Isoniazid Antibiotic 20 <1

Methyldopa Psychoactive drug 19 <2

Chlorpromazine Antipsychotic 20–50 <1

Sulfasalazine Rheumatoid arthritis 10 <1

Carbamazepine Epilepsy and neuropathic pain 1–25 <1

IFNα Hepatitis B and hepatitis C 11–53 <1

Anti-TNF

biologics

Rheumatoid arthritis

and seronegative

spondyloarthropathies

18–72 0.1–2.1

Prevalence

of clinical

manifestations (%)

Use of the specified drugs for >1 month might result in fever, musculoskeletal involvement and

serositis but usually without renal or neuropsychiatric involvement. Drug-induced systemic lupus

erythematosus (SLE) is usually milder than idiopathic SLE. Serological abnormalities include

homogenous antinuclear antibodies (ANAs) with antihistone antibodies. Withdrawal of the drug

generally leads to resolution of symptoms. IFNα, interferon-α; TNF, tumour necrosis factor.

activation products C3a and C5a and increased expression

of the endothelial cell surface adhesion molecules

E‐selectin, vascular cell adhesion molecule 1 (VCAM1)

and intercellular adhesion molecule 1 (ICAM1) in the

endothelium of patients with lupus flares 91 . In addition,

mesangial cells in the kidney can function as antigenpresenting

cells and keratinocytes in the skin can generate

self-antigenic material when undergoing UV‐induced

apoptosis, in both cases contributing to the development

of autoimmunity and SLE 92,93 . The renal podocyte is

partly responsible for proteinuria in lupus nephritis, and

abnormal expression of molecules or activity in processes

that protect against (for example, the kallikreins) or promote

podocyte injury or apoptosis have been described

in SLE 94 and might serve as new therapeutic targets.

Diagnosis, prevention and screening

Diagnosis versus classification

SLE is a heterogeneous autoimmune disorder with a

great variability in clinical manifestations and disease

severity, which can vary from mild to moderate and

severe. For example, skin inflammation might be limited

to the scalp in one patient, whereas the associated skin

rash might involve the scalp, trunk and upper extremity

in another patient. These issues must all be considered

when recruiting patients for clinical trials. Failure to

consider these issues in developing inclusion criteria for

trials may have been one of the reasons for failure of

recent clinical studies in SLE.

The diagnosis of SLE is made based on clinical

manifest ations and laboratory tests, including the

detection of autoantibodies, functional tests and imaging.

The majority of SLE manifestations are defined by

the presence of both subjective and objective findings.

Subjective findings include chest pains, arthralgias and

headaches, whereas objective findings include electrocardiographic

or echocardiographic confirmation of

cardiac comorbid ities, such as pleural or pericardial

pathology, joint deformities or skin rash, among others 95 .

In clinical practice, health care providers tend to use

the revised American College of Rheumatology (ACR)

classifi cation criteria for SLE 96,97 (BOX 4) for diagnosis,

although these criteria were originally developed to

classify and not to diagnose SLE. The main purpose

of classification criteria is to enhance the ability to identify,

in a standardized manner, a well-defined group of

patients. In general, classification criteria are applied in

clinical trials and in research settings to select a homogenous

group of patients 97,98 . Classification criteria

require a very high specificity and preferably a high

sensitivity. Conversely, diagnostic criteria require both a

high specificity and a high sensitivity, which is very difficult

to achieve 99 . The diagnosis of SLE is very challenging

because there are no generally accepted diagnostic

criteria. Recognizing the difficulty in developing diagnostic

criteria for rheumatic diseases, the ACR Classification

and Response Criteria Subcommittee of the Committee

on Quality decided not to consider funding or endorsing

diagnostic criteria.

It is important to note that the ACR classification

criteria for SLE do not capture the entire range

of manifest ations that can be encountered in patients

with SLE but focus on the more-prevalent manifestations.

For instance, the mucocutaneous manifestation

in the ACR classification criteria is focused on malar

rash (FIG. 3), photosensitivity, discoid lupus and oral ulcers

(BOX 4). Other skin manifestations, such as subacute cutaneous

lupus (annular (ring-shaped) and psoriasiform

(flaking)) and other forms of chronic cutaneous lupus

(lupus panniculitis or profundus and lupus erythematosus

tumidus), are not represented and therefore do

not count towards the classification criteria, which is a

drawback for the use of these criteria in a diagnostic setting.

Another example is the neurological system, which

is very poorly represented in the ACR classification

criteria and includes only two syndromes (seizures and

psychosis) and lacks other important syndromes, such

as organic brain syndrome, cranial nerve involvement,

SLE-associated headache and cerebrovascular accident,

among others 100 . Despite these disadvantages of the ACR

classification criteria to diagnosis SLE, they have served

a practical function when applied to recruiting patients

with SLE for clinical trials and cohort studies.

In general, the ACR classification criteria for SLE have

more practical value for patients with advanced disease.

This can be explained by the fact that the ACR classification

criteria require the presence of four or more items to

meet the definition of SLE. However, it is not unusual for

patients with SLE to have fewer than four criteria present

at the onset of the disease. Patients with SLE continue to

accrue SLE-specific clinical findings and autoantibodies

over time 97,101 .

The current ACR classification criteria have a sensitivity

of 86% and a specificity of 93%. The Systemic Lupus

International Collaborating Clinics (SLICC) recognized

the disadvantages of the ACR classification criteria lacking

many cutaneous and neuropsychiatric manifestations

and serum complement levels and proposed the



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

Endosome

PDC

TLR

Nucleic

acid

Type I IFNs

DC

Antigen

T cell

T cell

CD40L

Enhanced

immune

response

Failure of

anergy

Fc receptor

NET

Cytokines

Antibody

Macrophage

PMN

CD40

Nucleic acid

sensor

Non-haematopoietic cell

Class switching

Increased

autoantibody

production

B cell

TLR

Autoantibody production

Complement activation

Tissue damage

Figure 2 | Immune dysfunction in SLE. Several environmental factors can trigger disease Nature onset Reviews and they | Disease can be Primers

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.



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 mm 3 on two or more occasions

• Lymphocytopaenia: <1,500 per mm 3 on two or more occasions

• Thrombocytopaenia: <100,000 per mm 3 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 classifi cation criteria for SLE in 2012 (REF. 98).

With the current SLICC classification criteria, it is possible

to meet the classification criteria with 4 of the 17

criteria (including at least one clinical and one immunological

criterion) or biopsy-proven lupus nephritis in

the presence of ANAs or anti-dsDNA autoantibodies.

Unfortunately, with the wide range of SLE manifestations

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

classifi cation 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 criteria 102 . The increased

sensitivity gives the SLICC classification criteria greater

validity, but the loss in specificity compromises them as

classification criteria 99 . 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 manifest ation. The use of

one of these sets of criteria over the other remains to be

tested in future trials and research studies 103 .

Assessment of disease activity

The assessment of disease activity is challenging because

of the multifaceted complexity of the clinical presentations

and their variation over time. Thus, at least in clinical

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 validated 104 (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 mortality

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 validated 104 . Prolonged remission

(inactive disease) is an infrequent outcome and only

occurs in ~2.4% of patients with SLE without treatment

106 . 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 group 107 . More

recently, a consensus definition of lupus low disease activity

(LLDAS) has been developed, but this requires further

external validation 108 .

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 reliable 110 and is accepted

as an independent outcome measure 111 . Damage in SLE

predicts future damage accrual and mortality 112 .



PRIMER

Figure 3 | Typical malar rash in a patient with SLE. Malar Nature rash Reviews (or butterfly | Disease rash) Primers is a

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.

Comorbidities

As much as early diagnosis of SLE is important to initiate

the appropriate treatment and to prevent damage, capturing

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 SLE 113 .

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 women 114 . The prevalence of coronary

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 SLE 115 . 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,

particu larly 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 recommended for

the general population 117 .

Patients with SLE are at a high risk of developing

osteo necrosis, which might result in pain. Diagnosis

of osteonecrosis involves radiographs, bone scans, tomograms

or magnetic resonance images (FIG. 4). Osteopenia

has been reported in 25–74% and osteoporosis in 1.4–68%

of patients with SLE 118 . Risk factors for low bone mineral

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 secondary

to myositis, among other factors) 118 . Identification of

such factors is essential for risk stratification and for the

develop ment of preventive measures against low bone

mineral density in the future.

Cognitive impairment is one of the most common

manifestations of neuropsychiatric SLE with frequencies

of up to 80% reported 119 . A wide variation in the

prevalence of cognitive impairment has been reported,

owing to the lack of standardized definitions and valid

metrics of cognitive impairment 120 . The pathogenetic

mech anisms of SLE-associated cognitive impairment are

unclear, but cognitive impairment requires early diagnosis

and the development of interventions to prevent the

accrual of long-term damage and disability.

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 simultaneously,

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 process.

The intensity of treatment is adjusted to the severity

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 topical

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 revisions 100,187,188 ) 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

revision 189,190 ). 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 Index 192 and

BILAG-based Composite Lupus Assessment 180 ). A measure

to summarize disease activity over time — the Adjusted

Mean SLEDAI‐2000 (AMS) — has also been developed 193 .



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 synthesis

that blocks immune cell proliferation) are often coprescribed

with antimalarials in non-renal SLE. However,

because immunosuppression can cause adverse effects,

including bone marrow suppression or liver test abnormalities,

blood tests must be monitored during use for

these changes.

Figure 4 | Multifocal osteonecrosis in a patient with SLE Nature following Reviews long-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 NSAIDs 121 .

More-severe SLE disease activity often requires systemic

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 therapy

varies in practice. Minimizing total dosage is vital

to prevent signifi cant steroid-induced comorbidities,

yet undertreatment can lead to insufficient immunosuppression

and tissue damage accrual. More-persistent

or severe joint or skin involvement often involves using

oral prednisolone (<0.5 mg per kg) while intravenous

methyl prednisolone 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 immunosuppressive

agents require weeks to become effective.

Antimalarials that are used for their immunosuppressive

actions, for example, hydroxychloroquine or, less commonly,

quinacrine (also known as mepacrine) or chloroquine,

are commenced immediately. The LUMINA study

suggested that hydroxychloroquine is well tolerated and

is associated with prolonged lifespan 122 , effects that are

potentially mediated by reducing flares 123 , 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 improvement

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 monoclonal

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 positivity

and low complement levels than in patients with SLE

with lower levels of these markers 125 . 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 activity,

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 androgens

and oestrogens, can improve overall disease activity

and enable reduction in glucocorticoid dosage with

minor adverse effects of hirsutism (excessive hairiness)

or acne 127 . 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 danazol 128 .

Thalidomide (an immunomodulatory drug) has successfully

been used in the treatment of cutaneous lupus 129 , but

shows toxicity (especially peripheral neuropathy) and is

contraindicated in women of childbearing age.

While fatigue, joint pains, muscle aches and cognitive

symptoms are common in patients with SLE, they do

not always represent disease activity. These symptoms are

similar to fibromyalgia, which may coexist with SLE 130 .

Complicating the clinical picture, thyroid dysfunction 131 ,

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



PRIMER

these associated symptoms, and use of other thera pies

such as centrally acting pain-modulating agents and

antidepressants may be required. In particular, fatigue

can be very resistant to treatment with non-drug therapies,

particularly aerobic exercise, which is important in

combatting this.

Management of active lupus nephritis

The best-studied SLE manifestation is lupus neph ritis,

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

(immunization with inactivated

autoreactive T cells) 194

B cells

Rituxilup (a combination

of rituximab and a single

intravenous dose of

corticosteroids, followed by

mycophenolate mofetil) 137

Rituximab (LUNAR trial) 142

Ocrelizumab 195

Epratuzumab 180,181

Belimumab 125

Atacicept 196

Depletion of autoreactive

T cells

Chimeric anti‐CD20 antibody

(B cell depletion)

Chimeric anti‐CD20 antibody

(B cell depletion)

Human anti‐CD20 antibody

(B cell depletion)

Anti‐CD22 antibody

(inhibits B cell receptor

signalling)

Inhibitor of BAFF

(also known as TNFSF13B)

Blockade of BAFF and APRIL

(also known as TNFSF13)

Improved SLEDAI score and SLE remission in refractory SLE

Remission of lupus nephritis in an open-label study

RCT showed no difference between rituximab and placebo when used with

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

Study discontinued owing to high rate of infection

Phase IIb study that suggested improvements in BILAG-based end point

combined lupus assessment, but recent phase III data cast doubt on efficacy

over conventional treatment

Significant reduction in SELENA-SLEDAI scores versus controls on conventional

treatment

75 mg of atacicept did not improve flare or flare rate compared with placebo;

a trial testing higher doses (150 mg) was terminated owing to two deaths

Blisibimod 197 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

Tabalumab 198 Blockade of BAFF Mixed results in two phase III trials and drug development discontinued by the

pharmaceutical company

dsDNA

Abetimus sodium (LJP 394) 199

Cytokines

Crosslinks dsDNA receptor on

B cells

Intention-to‐treat analysis showed no difference in frequency or time to

renal flare

Infliximab 200 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

Anakinra 201 IL‐1 inhibitor Uncontrolled open-label study showed improvement in tender joints with

subsequent worsening

Sirukumab and PF‐04236921

(REF. 202)

Anti‐IL‐10 and B-N10

(REF. 203)

Sifalimumab 204

Blockade of IL‐6 signalling

Inhibition of IL‐10 signalling

(suppression of T H

1 response)

Suppression of IFNα activity and

attenuation of other cytokines

Anifrolumab 205 Antagonist of IFNα receptor 1,

which binds sterically to the

IFN receptor, preventing

the formation of a ternary

signalling complex

Mixed results: sirukumab was associated with infections and drug development

was stopped; PF‐04236921 showed good effects and further studies are in progress

Small (six patients) uncontrolled study showed mild improvement in the SLEDAI

score from 8 to 3

Reduction in disease activity across several measures in a phase IIb study

Phase II RCT of 305 treatment-resistant patients with SLE demonstrated

significant improvement in primary composite end points of SRI and a reduction

in corticosteroid usage

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; T H

1, T helper 1; TNF, tumour necrosis factor.



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 comorbidities 132–134 . 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 immunosuppressive

mycophenolate mofetil 136 . 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

preferred 138 . In 2002, the Euro-Lupus randomized trial

of 90 patients with SLE with proliferative glomerulonephritis

demonstrated that a reduced-dosage cyclophosphamide

regimen followed by azathioprine was as

effective as higher-dose intravenous cyclop hosphamide,

but was associated with considerably less tox icity 139 .

Later trials demonstrated that mycophenolate mofetil

was at least as effective for the treatment of lupus nephritis

as cyclophosphamide 138 . The 10‐year follow-up of

the Euro-Lupus low-dose cyclophosphamide cohort

demonstrated similar outcomes to the high-dose cyclophosphamide

group 140 . While glucocorticoid initiation

remains ‘best practice’, with the evidence to date, additional

initiation therapy with mycophenolate mofetil

is now an established option, with intravenous cyclophosphamide

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

immunosuppressants 141 . Despite this, the 52‐week randomized,

double-blind LUNAR clinical trial of rituximab

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

mofetil 143 . The investigator-initiated, randomized RING

trial is currently addressing whether the addition of

rituximab to standard of care with azathioprine, mycophenolate

mofetil or intravenous cyclophosphamide

improves renal response rate after 104 weeks 144 .

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 relapses 145,146 . 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 intravenous

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 useful

particularly when infection may preclude the use of

immunosuppressive agents 147 .

Quality of life

SLE can exert a profound effect on the life of patients,

both qualitative and quantitative, with higher mortality

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 life 148 . The physical and mental components

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 working

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 produc tivity and professional development has been

found using a survey of 2,070 patients with SLE 150 .

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 reviewed 151 .

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



PRIMER

Table 4 | Outcome measures used to examine quality of life in SLE

Aim of study Findings Measures and instruments

Fatigue

To determine the link between affective states,

personality traits and mental health status

with SLE-associated fatigue in 57 Caucasian

patients 206

To determine the best instruments to assess

fatigue in SLE 207

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 impairment 208

To compare changes in QOL in 715 patients with

SLE from three countries (the United States,

Canada and the United Kingdom) over 4 years 209

Physical functioning

To assess if disease activity was associated with

physical functioning in 96 patients with SLE 210

To determine baseline factors that are predictive

of HR‐QOL 211

To assess a total of 552 patients with SLE using

SF‐6D (a self-reported measure of HR‐QOL),

which produces a single numerical value 212

Work disability

Psychological distress and personality trait

patterns in SLE-associated fatigue similar to

patients with chronic pain. Depression was

significantly associated with fatigue

Using literature searches and consensus

opinion from experts, 15 fatigue instruments

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

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

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

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

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

mortality in patients with SLE

Several self-reported and assessed variables Rate of self-reported work disability was 19%

including poverty, education, sex, race and at 5 years and was higher for African-American

disease activity measured in 273 patients with individuals (25%) possibly owing to higher

SLE in the LUMINA cohort 213 damage accrual and poverty compared with

Caucasian individuals and Hispanic individuals

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 rates 214

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 years 216

26 studies representing 9,886 patients with

SLE were included. About 32.5% of patients

were work disabled. Reduced employment was

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

health care-related costs. They are higher in

the United States than in the United Kingdom

and Canada but are not associated with

better outcomes

Direct health care costs correlate with worse

disease activity and are mainly owing to

hospitalizations and medications

FSS, Personality defined with Minnesota

Multiphasic Personality Inventory 2 and mental

status by Beck Depression Inventory

Several fatigue instruments including SLAM,

FSS and SLEDAI

ANAM

SF‐36 physical and mental component scores

HAQ

SF‐36

SF‐6D

Several indices including illness behaviours,

learned helplessness (Rheumatology Attitude

Index), social support (Support Evaluation List),

SF‐36, Pain Visual Analogue Score, HR‐QOL

and the Arthritis Self-Efficacy Scale

Systematic review of 135 titles from the United

States, Canada, the United Kingdom and

Sweden, among others

Several measures including lost productivity,

disease activity and social support

Retrospective analysis of medical records. Flare

activity (SLEDAI Flare Index), disease activity

(SLEDAI), tissue damage (SLICC) and health

care use were measured

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.



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 QOL 148,152 .

Fatigue affects QOL profoundly 148,153 and is present in up

to 80% of patients with SLE 153 . 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, studies

suggest that treatment with calcifediol (a vitamin D

precursor) results in a small but significant reduction

in fatigue in patients with vitamin D‐deficient SLE 155 .

In addition, post hoc analysis of randomized controlled

trials of belimumab have shown a decreased degree of

fatigue among responders 156 , although this drug cannot

be recommended exclusively for the treatment of SLEassociated

fatigue. Recently, a study of 1,827 patients

from the SLICC cohort confirmed the effect of mood

disorders on the QOL of patients with SLE 157 .

It is important to remember that many drugs

used to treat SLE can cause serious adverse effects,

particularly glucocorticoids. Moreover, the marked

changes in phys ical appearance caused by steroid therapy

can be devastat ing, particularly in young female

patients 158 . Thus, it is not surprising that glucocorticoids

are consistently identified as one of the major

predictors of decreased QOL 148,153 . While lowering

gluco corticoid doses is strongly recommended, treating

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 diagnosis 159 . 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

hydroxychloro quine or glucocorticoids early in disease

development had a delayed onset of a formal SLE diagnosis,

which required four or more ACR criteria 161 (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 1980s 10 . 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

damage 163 as well as disease activity 91 . Other urinary biomarkers

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 nephritis 164 .

Diagnosing neuropsychiatric SLE remains a challenge.

Functional MRI can detect certain phenotypes

including stroke. A subset of dsDNA-specific antibodies

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 mice 165,166 .

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 associated

with SLE and especially longer SLE duration 167 .

The overall risk of CVD is estimated to be between 2.6

(REF. 168) and 10‐times higher 169 in patients with SLE than



PRIMER

Patient evaluation

Blood tests

ECG

Lung function test

Chest X-ray

OGD and colonoscopy

CT or PET

Conditioning regimen

Intravenous cyclophosphamide

and rabbit anti-thymocyte globulin

Injection of stem cells

Antibiotics

Antivirals

Antifungals

Engraftment for 10–14 days

in the general population, even allowing for traditional

risk factors. EULAR guidelines suggest that patients with

SLE should be monitored for CVD risk. However, specific

recommendations cannot yet be made as we do not know

which strategies are best to reduce the CVD burden in

SLE. It would make sense to identify patients at risk, control

disease activity and modify traditional risk factors,

but longitudinal studies are lacking in this respect 170 .

Preventive strategies for CVD are likely to be better

because patients with SLE have a higher in‐hospital

mortality and morbidity after coronary percutaneous

intervention, even after adjustment for traditional risks

and comorbid conditions 171 . Complications such as the

‘lipid paradox’, in which CVD risk can be higher in those

with lower total and LDL cholesterol, only add to the

uncertainty of which parameters are best to modify 172 .

Mobilization of stem cells

With intravenous cyclophosphamide and GM-CSF

Collection of CD34 + stem cells

Via apheresis

Stem cell storage

Liquid nitrogen and DMSO until use

Thaw stem cells

Figure 5 | Stem cell transplantation in SLE. Stem cell transplantation has been used

Nature Reviews | Disease Primers

in mouse models of systemic lupus erythematosus (SLE) and in patients who failed

conventional treatments and biologics. Conventionally, haematopoeitic stem cells

have been used, but the multipotent mesenchymal stem cells from bone marrow,

which normally make cartilage, bone and adipose tissue, might reduce the need

for myeloablative therapy in refractory SLE in future. DMSO, dimethyl sulfoxide;

ECG, electrocardiogram; GM‐CSF, granulocyte–macrophage colony-stimulating factor;

OGD, oesophagogastroduodenoscopy.

Treatment targets

Studies from various clinical conditions clearly demonstrate

the benefit of disease-specific treatment targets.

An international task force recommended several principles

of treat‐to‐target management in SLE; the target

for treatment should be remission, prevention of damage

and disease flares and minimization of glucocorticoid

usage, among others 173 . Unlike rheumatoid arthritis,

measurement tools to define remission or prevention,

such as BILAG or SLEDAI‐2K, are not widely used in

clinical practice as they are perceived to be cumbersome

and time-consuming. In addition, the definition of

remission in SLE has not been validated, nor which variables

should be considered to define remission. Studies

point towards better outcomes using remission targets in

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 accepted 176 (BOX 6).

A study in Caucasian patients found that, although complete,

prolonged remission (grade A) was possible in

7% of patients and significantly more patients achieved

remission on medication with or without low-dose glucocorticoids

(~15% in each category (grade B and grade C)).

Compared with previous studies using similar categories,

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 strategies

with the wider acceptance that controlling damage,

especially in renal SLE, is paramount.

Important questions for the future are how long

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.

Future therapies

Recently an expert panel has developed treat‐to- target

guidance for SLE 173,178 . This is complicated for SLE

because, in contrast to other diseases, the heterogeneity

of the condition means that several therapeutic targets

may have to be considered simultaneously.

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 compromised

trial design and unexpected results. Rituximab

was feted as an effective targeted drug for lupus nephritis,

but the LUNAR and EXPLORER trials did not meet

end points for significance 143 . Trial design was compromised

by factors such as steroid usage and very stringent

end points that may have led to an underestimation

of effect.

Guidance on drug development trials in SLE was

produced in 2010 by the US FDA 179 . However, future trials

must address the issues of disease prevention and early

intervention to prevent damage accrual. Encouraging

the use of organ-specific measures, such as Cutaneous

Lupus Erythematosus Disease Area and Severity

Index (CLASI) for skin, and specific QOL measures,

such as Lupus Patient-Reported Outcome (LupusPRO)



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 cellmodulating

agent epratuzumab (anti‐CD22) 180 , IFN

antagonists and IL‐6 and IL‐10 blockers (TABLE 3). While

two phase III trials with epratuzumab 181 failed to achieve

their primary end points, there is still hope that with further

trials and analyses, patient subgroups may respond

to these newer therapies, as happened with the LUNAR

trial of rituximab 142 .

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 features 57 . Future strategies must

also minimize the long-term effect of glucocorticoids.

Studies of rituximab in lupus nephritis point to how

this could work in practice 137 . Combination therapy of

targeted therapeutic agents might lead to synergistic

actions with clinical trials using combinations of rituximab,

belimumab and cyclophosphamide 182 . Innovations

include the construction of potentially effective novel

bispecific proteins 183 . Replacement of the dysfunctional

immune system with a normal one will be another fruitful

strategy. First, altering the SLE genotype through the

use of vectors (viral vectors or naked plasmids packaged

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 pending

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 risk 185 (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, placebocontrolled

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, longterm

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).



PRIMER

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

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

immuno stimulatory 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


(2003).

67. Gergely, P. Jr et al. Mitochondrial hyperpolarization

and ATP depletion in patients with systemic lupus


(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


(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

systemic lupus erythematosus. Ann. Rheum. Dis. 69,

305–308 (2010).

78. Zhu, H. et al. Autoantigen microarray for highthroughput

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


(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.


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).

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 dosedependent

manner: a population based cohort study.


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.

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.


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 healthrelated

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.


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.



PRIMER

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).

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.


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 moderateto‐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, placebocontrolled

clinical trial of blisibimod, an inhibitor of

B cell activating factor, in patients with moderateto‐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


(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).

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-andreduction-of-severe-flares-following-subcutaneousadministration-of-an-il-6-monoclonal-antibody-mabin-subjects-with-active-generalized-systemic-lupuserythematos/

(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.


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.



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