SYSTEMIC LUPUS ERYTHEMATOSUS

Advances in systemic Key points

lupus erythematosus C Systemic lupus erythematosus (SLE) is a complex disease with
multisystemic involvement
Su-Ann Yeoh
Sofia Sapeta Dias
C It is more common in female patients

David A Isenberg C There is a higher prevalence of SLE in patients with African

heritage, with more severe disease and poorer clinical
outcomes
Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease C Classification criteria and tools to measure disease activity
with a heterogeneous course and systemic involvement. It is the result should be used in clinical practice
of a complex pathogenic pathway that culminates in autoantibody for-
mation. The interaction between environmental triggers and genetic C The Systemic Lupus International Collaborating Clinics classi-
susceptibility is key in this process. Genome-wide association study fication criteria (2012) are more sensitive than the revised
technology has allowed the recognition of >80 loci associated with American College of Rheumatology criteria, requiring at least
SLE that lead to the formation of key proteins, each contributing a one clinical and one immunological feature to be present
small increase to the risk. Advances in the management of the disease
include new validated standardized tools to capture disease activity, C Biological agents are effective for treating different features of
damage and quality of life, for clinical and research purposes. The SLE and have an important corticosteroid-sparing effect
prognosis of SLE has much improved in the last 50 years because
of better general management and specific treatment, including better
use of immunosuppressive agents and development of a new group of
drugs e biological therapies. prognosis, and measuring response to treatment. This approach
Keywords Disease activity index; management; MRCP; pathogen- is particularly important now that new biological drugs are
esis; systemic lupus erythematosus; treatment beginning to show encouraging signs of efficacy in lupus. This
review focuses mostly on the recent advances in understanding
and managing SLE.

Introduction Understanding
Systemic lupus erythematosus (SLE) is a chronic multisystemic Epidemiology
autoimmune disease with a highly heterogeneous pattern of SLE is a rare disease. Its incidence is estimated to be 1e10 per
clinical and serological manifestations. Its course differs in 100,000 personeyears, and its prevalence 20e200 per 100,000.1,2
different individuals and is unpredictable within the same patient The incidence may be increasing, probably because of greater
over time, which makes it interesting and challenging to manage. awareness of the disease. The prevalence has also been thought
The pathogenesis of SLE is the result of interactions between to be increasing, which may reflect an improvement in survival
genes, hormones and the environment, but its precise aetiology rates as well as chronicity.
is mostly unknown. Recently, >80 risk genes for the disease have SLE is more frequent and more severe in African, Hispanic,
been described. Certain genetic features are also associated with Chinese and Asian descendants. These patients have more hae-
increased disease activity. matological, serosal, neurological and renal manifestations in
In the last 30 years, major efforts have been made to define general, although clinical profiles vary in specific populations.
some key aspects of the condition, notably disease activity and Study of the LUMINA (Lupus in Minorities: Nature vs Nurture)
damage, using standardized indices. These tools are essential for cohort concluded that, especially in African-American and His-
comparing different cohorts, assessing disease progression and panic populations (from Texas), there is an association with high
disease activity and damage. Besides ethnicity, other predictors
of damage are age, disease duration, disease activity and corti-
Su-Ann Yeoh BMedSci BMBS MRCP is a Specialty Registrar in costeroid use.3
Rheumatology, University College Hospital London, UK. Competing Socioeconomic status is also associated with a worse prog-
interests: none declared. nosis, particularly with respect to the later manifestations of the
Sofia Sapeta Dias MD is a Consultant in Internal Medicine in the disease. Poor social support is more commonly found among
~o Jose
Neurocritical Care Unit, Hospital de Sa , Centro Hospitalar ethnic minorities, which makes it difficult to distinguish if this is
Lisboa Central, EPE, Lisbon, Portugal. Competing interests: none an independent contributor to disease severity.1
declared. SLE is more frequent among women of childbearing age, in a
David A Isenberg MD FRCP FAMS is Academic Director of ratio that varies between populations but is on average 10:1.
Rheumatology at University College London, UK. Competing Although the age of diagnosis also depends on ethnicity, it is
interests: none declared. most commonly described as the third and fourth decades of life.

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 SYSTEMIC LUPUS ERYTHEMATOSUS

Males and female patients show little difference in their disease describes a higher prevalence of SLE in the Afro-Caribbean
manifestations or severity, although presentation at the extremes population living in Europe and North America, whereas the
of life is associated with increased severity. prevalence in Western Africa is very low.1 However, this
observation may result from an environmental influence on the
Pathogenesis manifestations of SLE or from inadequate health systems in Af-
There is a complex interaction between gene susceptibility, rica that fail to recognize the condition.
hormonal influences and environmental triggers with a break- Infections can modulate the immune system protecting
down of immune tolerance, resulting in autoantibody production against autoimmunity, but can also trigger the disease. An as-
and consequent dysregulation of the inflammatory response, sociation between SLE and EpsteineBarr virus (EBV) infection
leading to induction and maintenance of the disease. has been described in children; this virus can trigger a flare
because of antigenic mimicking (EBV protein EBNA-1 can cross-
Genetic factors react with the self-antigen Ro).3 An association between cyto-
A genetic component in SLE pathogenesis was first suggested by megalovirus and SLE has also been suggested.
evident concordance between monozygotic twins in 24e69% of Oestrogens increase the risk of the disease and are a recog-
cases, compared with 1e5% in dizygotic twins,1,2 and also by nized trigger for flares, which probably contributes to the higher
the different prevalence in various ethnic groups. An 8e20-fold prevalence of SLE in women. Women treated with hormonal
increased risk of developing SLE has been reported in siblings replacement therapy (but less so with oral contraceptives) have a
of SLE patients.2 higher risk of developing SLE3 and also a higher risk of mild to
In the last decade, with the development of genome-wide moderate flare; in addition, associations between SLE and early
association study technology, >80 loci with common variants menarche, menstrual irregularities and early or surgical meno-
have been shown to have a confirmed association with SLE. pause have been described.
These genes lead to the formation of key proteins involved in Other environmental triggers reported include ultraviolet
innate and adaptive immunity. Each appears to make a small light, cigarette smoking and silica. Drugs implicated in drug-
contribution to the complex pathogenesis of lupus, suggesting induced lupus include hydralazine, D-penicillamine, minocy-
that they work cumulatively. cline, lithium and more recently tumour necrosis factor (TNF)-a
One of the chromosomal regions having the strongest asso- blocking agents.3
ciation with SLE is the human leucocyte antigen (HLA) locus,
especially the class II region containing HLA-DRB1, -DQA1 and Pathological mechanisms
-DQB1. There are also associations of some of these loci with The complex pathogenesis of SLE seems to involve almost every
specific clinical features (e.g. DRB1 and renal disease) and component of the immune system that culminates in antibody
serological features (e.g. DR2 and anti-Sm antibodies, and DR3 formation. The principal mechanisms are listed here.2
and anti-Ro antibodies).2
Although hormonal influences have a greater importance in B and T cell signalling abnormalities include an abnormal T
determining the higher prevalence of SLE in women, some X- cell receptor complex, alterations on proteins that influence the T
chromosome-linked genes have been described that might cell response to inflammation in various ways (such as mitogen-
contribute to this (e.g. IRAK1, its neighbour gene MECP2 and activated protein kinase), decreased concentrations of blunting
presence of CD40L).2 molecules such as Lyn (LCK/Yes-related novel tyrosine kinase),
In the last decade, the importance of the interferon (IFN) impaired signalling via the B cell inhibitory receptor FcgRIIB, and
signature in the pathogenesis of SLE has been recognized. IFNa is a faster response to a B cell proliferation stimulus such as a
a key mediator in activation of the innate response and also in proliferation-inducing ligand (APRIL) or B lymphocyte stimulator
the adaptive immune system (normally in response to a viral (BLyS).
infection). It enhances natural killer cell activity, stimulates
maturation of antigen-presenting cells, prevents apoptosis of T Autoantigen-specific T cells have been described. T cells stim-
cells, suppresses regulatory T cells and promotes B cell differ- ulate B cell proliferation and are necessary for the secretion of
entiation and antibody production. In patients with SLE, IFNa high-affinity class-switched immunoglobulin (Ig) G antibodies, in
expression is increased in the absence of appropriate stimuli, a process called T lymphocyte help. These antibodies are
because of overexpression of the regulating genes, and IFNa strongly associated with tissue damage in SLE. T regulatory cells,
concentration is associated with disease activity.2 which suppress T helper cells and B cells, are impaired in SLE.
It is also now realized that post-translational modifications are
likely to be contributors to the complex inheritance and incom- Dysregulated apoptosis and defective clearance of cellular
plete concordance between homozygotic twins. In SLE, epige- debris increases autoantigen exposure and tolerance breakdown.
netic modifications such as abnormalities in DNA methylation In SLE, apoptosis (particularly of T lymphocytes) is dysregulated
and histones have been reported.2 For example, an elevated in a Fas/Fas ligand-dependent pathway that is hyperexpressed
interleukin (IL)-6 concentration may contribute to the prolifera- and correlates with SLE activity and autoantibody concentra-
tion of B cells via DNA methylation. tions. Abnormalities in the innate immune system, including that
of phagocytes and complement, are also linked to impaired
Environmental influences and triggers recognition and clearance of apoptotic bodies. Subsequently,
The importance of the environment has been suggested by abnormal prolonged exposure of nuclear antigens that undergo
epidemiological studies. The ‘prevalence gradient hypothesis’ multiple alterations creates neoepitopes or uncovers hidden

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 SYSTEMIC LUPUS ERYTHEMATOSUS

epitopes. The remaining apoptotic bodies then go through a patients with SLE; the presence of each of these correlates with
process called secondary necrosis that leads to the release of specific clinical manifestations (Table 1).
even more nuclear material. However, the pathogenic role of the autoantibodies in SLE is
Neutrophil extracellular traps (NETs), a mechanism of not entirely clear. They are found in kidney biopsies, where they
defence against microorganisms, also play an important role in bind directly to renal cells or via immune complexes with
perpetuating the inflammation and exposure of double-stranded circulating nuclear components, which are then deposited in the
(ds) DNA because they are not promptly degraded in SLE. The renal glomerular basement membrane (leading to inflammation).
lower degradation of NETs in SLE correlates with disease However, the hypothesis of secondary binding to an already
activity. inflamed tissue is not excluded. In this case, the presence of
autoantibodies would be a marker, not a cause, of inflammation.
Antibody formation occurs, with pathogenic potential. The Another suggestion is that anti-dsDNA antibodies are binding to
presence of hyperactive and hyper-responsive B and T cells and nucleosomes; in other words, dsDNA is linked to histones, and
the prolonged exposure to nuclear antigens leads to the forma- the histones (which are positively charged) are responsible for
tion of autoantibodies directed against nuclear structures that are binding to negatively charged regions of renal tissue e the so-
the immunological hallmark of SLE. called histone bridge theory. Autoantibodies lead to the forma-
Autoantibodies have been reported to be found in the serum tion of immune complexes that directly induce B cells to produce
up to 10 years before symptom onset in 85% of SLE patients.2 more autoantibodies and enhance the Toll-like receptoreIFN1
Deposition of autoantibodies and complement with inflamma- pathway, which also stimulates B cells to differentiate into
tion is identified in biopsies of various tissues from patients with plasmablasts.
SLE. The most widely studied antibody is anti-dsDNA, the serum It is important to bear in mind that different autoantibodies
concentration of which often correlates with disease activity. have different specificities and sensitivities. Table 1 shows the
Other antibodies have been identified in biopsies and serum from autoantibodies that may be present in SLE. Anti-nuclear antibody
(ANA) has 95% sensitive but lacks specificity. It is present up to

Pathogenic autoantibodies in SLE

Autoantibodies Prevalence Sensitivity Specificity Clinical manifestations Other diseases
in SLE (%) in SLE (%) in SLE (%)

Anti-nuclear >95 High Low Scleroderma, Sjo €gren’s syndrome, rheumatoid

antibody arthritis, polymyositis, dermatomyositis, drug-
induced lupus, infection, malignancy, drugs,
other autoimmune diseases
Anti-dsDNA 70e80 Moderate High Renal, skin Rare in other diseases
Anti-nucleosome 60e90 High High Renal, skin Mixed connective tissue disease, autoimmune
hepatitis, scleroderma, Sjo€gren’s syndrome
Anti-Ro/SSA 30e40 Moderate Moderate Sicca symptoms, renal, skin, fetal, heart €gren’s syndrome, rheumatoid arthritis,
Sjo
abnormalities, rash in newborn polymyositis, scleroderma
Anti-La/SSB 15e20 Moderate Moderate Fetal heart abnormalities €gren’s syndrome
Sjo
Anti-Sm 10e30 Low High Renal, neuropsychiatric associations with Rare in other diseases
higher mortality
Anti-U1-RNP 25 Raynaud’s phenomenon, lung, Mixed connective tissue disease, scleroderma,
neuropsychiatric, musculoskeletal €gren’s
polymyositis, rheumatoid arthritis, Sjo
syndrome
Anti-ribosomal P 10e40 Moderate Moderate Neuropsychiatric hepatitis
Anti-NMDA 33e50 Neuropsychiatric Anti-NMDA receptor encephalitis
Anti-phospholipid 20e40 Low Low Thrombosis, pregnancy loss Malignancy, infection, drugs
Anti-a actinin 20 Renal
Anti-C1q 30e50 Low Low Renal Hypocomplementaemic urticarial vasculitis,
€gren’s syndrome, rheumatoid vasculitis
Sjo
Anti-histone 70e80 Low Low Drug-induced lupus Scleroderma, rheumatoid arthritis, Sjo€ gren’s
syndrome, mixed connective tissue disease,
vasculitis, malignancy, liver disease

Adapted from Rahman A, Isenberg DA. Systemic lupus erythematosus. N Engl J Med 2008. 358:931; and Lloyd P, Doaty S, Hahn B. Aetiopathogenesis of systemic lupus
erythematosus. In: Systemic Lupus Erythematosus. Oxford, UK: Oxford University Press; 2016.3

Table 1

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 SYSTEMIC LUPUS ERYTHEMATOSUS

20% of the normal healthy population, as well as in other types

of autoimmune disease, malignancies, infections and medication SLICC classification system for SLE
use. A higher ANA titre, especially 1:640 and above, is consid- Clinical criteria
ered significant and might suggest the presence of an autoim- C Acute cutaneous lupus including:
mune condition. A homogenous pattern of ANA is seen in
Lupus malar rash (do not count if malar discoid)
patients with SLE and linked to anti-dsDNA and anti-nucleosome
Bullous lupus
antibodies, whereas a speckled pattern is linked to antibodies
Toxic epidermal variant of SLE
against extractable nuclear antigens.
Maculopapular lupus rash
Anti-Sm and anti-dsDNA are both rare in other rheumatic dis-
Photosensitivity lupus rash
eases and are highly specific, but have low and moderate sensi-
Or subacute cutaneous lupus
tivity, respectively. Anti-Sm antibodies, which are three times as C Chronic cutaneous lupus, including:
common in black than white patients, are associated with higher
Classic discoid rash, localized (above the neck) or generalized
mortality and morbidity. Anti-dsDNA enzyme-linked immuno- (above and below the neck)
assay (ELISA) is used in clinical practice to monitor lupus activity,
Hypertrophic (verrucous) lupus
unlike with anti-Sm, whose levels do not correlate with disease
Lupus panniculitis (profundus)
activity. DNA Crithidia assay is another test that can be used in the
Mucosal lupus
diagnostic process; which is more specific than ELISA.3
Lupus erythematosus tumidus

Chilblains lupus
Classification criteria

Discoid lupus/lichen planus overlap
The American College of Rheumatology (ACR) classification C Oral ulcers
criteria, first published in 1971 and subsequently revised in 1982

Palate e buccal or tongue
and in 1997, have been the most widely used. In 2012, the Sys-

Or nasal ulcers
temic Lupus International Collaborating Clinics (SLICC) group C Non-scarring alopecia
published validated criteria that have higher sensitivity than the C Synovitis involving two or more joints, characterized by swelling
revised ACR criteria. They also have lower specificity (although
or effusion Or tenderness in two or more joints and at least
not statistically significant), which might lead to the inclusion of
30 minutes of morning stiffness.
more patients in clinical trials. Furthermore, the SLICC criteria
C Serositis
showed some changes that might improve their use in clinical

Typical pleurisy for >1 day
practice. Some criteria (e.g. photosensitivity, malar rash) were

Or pleural effusions
reorganised in order to minimise overlaps, while others (e.g.

Or pleural rub
neurological manifestations, arthritis) were redefined. Among

Typical pericardial pain
the immunological criteria, ANA, anti-dsDNA, anti-Sm and

Or pericardial effusion
antiphospholipid antibodies are now considered different

Or pericardial rub
criteria, so each can contribute to the classification of SLE. Low

Or pericarditis by electrocardiography
complement is a new criterion.
C Renal
Using the SLICC classification, at least four criteria from a list

Urine protein:creatinine ratio (or 24-hour urinary protein)
of clinical and immunological features (Table 2), including at
representing 500 mg protein/24 hours
least one clinical criterion and one immunological criterion,

Or red cell casts
should be present for a patient to be deemed to have SLE.
C Neurological
However, biopsy-proven lupus nephritis (LN) together with ANA

Seizures
and anti-dsDNA may also be sufficient. The mandatory presence

Psychosis
of clinical and immunological features is useful to avoid

Mononeuritis multiplex
including patients without clinical manifestations or without

Myelitis
positive antibodies.4

Peripheral or cranial neuropathy

Acute confusional state
Management
C Haemolytic anaemia
Clinical features C Leucopenia (<4000/mm3) at least once
SLE has an unpredictable course. It progresses in acute flares and Or lymphopenia (<1000/mm3) at least once
periods of remission, although there are probably long periods of C Thrombocytopenia (<100,000/mm3) at least once
subclinical inflammatory activity. It can affect virtually every
organ and system in the body, and during the flares more than Immunological criteria
one organ is usually affected (Table 3). In mild forms, the joints C Antinuclear antibody (ANA)
and skin are the main organs affected. In moderate forms, other C Anti-dsDNA antibody
organs are involved, but it is severe disease, notably of the kid- C Anti-Sm
neys and heart, that can be life-threatening. C Antiphospholipid antibody positivity as determined by any of the
Renal involvement occurs in 30e50% of patients with SLE, following:
usually early in the disease course. It has been shown that anti-
Positive test result for lupus anticoagulant
dsDNA, anti-Sm, complement and anti-C1q antibodies are
False-positive test result for rapid plasma reagin

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 SYSTEMIC LUPUS ERYTHEMATOSUS

Medium- or high-titre anticardiolipin antibody Cumulative prevalence of clinical features in SLE

Positive test result for anti-b2-glycoprotein I
C Low complement Clinical feature Prevalence (%)
C Direct Coombs’ test in the absence of haemolytic anaemia
Dermatological
Using the SLICC classification, at least four criteria, including at least one clin- Alopecia 70
ical criterion and one immunological criterion, should be present to be classi- Oral ulceration 50
fied as having SLE.
Adapted from Petri M, Orbai AM, Alarco n GS et al. Derivation and validation of Butterfly malar rash 40
the Systemic Lupus International Collaborating Clinics classification criteria for Purpuric lesions 40
systemic lupus erythematosus. Arthritis Rheum 2012; 64: 2677e86. Vasculitic skin lesions 40
Discoid lupus 20
Table 2 Livedo reticularis 20
Erythematous maculopapular eruption <5
strongly associated with renal involvement. It is imperative that Relapsing nodular non-suppurative <5
blood pressure measurement and urine analysis are performed as panniculitis
part of the clinical assessment of patients with SLE. Renal biopsy Musculoskeletal
is performed to identify the presence of LN, which has six stages: Arthralgia/arthritis 90
stage I, minimal mesangial proliferative LN; stage II, mesangial Myalgia 50
proliferative LN; stage III, focal LN; stage IV, diffuse LN; stage V, Tenosynovitis 20
membranous LN; and stage VI, advanced sclerosis. It is also Myositis 5
important to be aware of other potential causes of renal impair- Cardiopulmonary
ment in SLE patients as a result of concurrent diseases or Valvular dysfunction 55
nephrotoxic drugs.3 Pleurisy 35
Neuropsychiatric SLE is highly diverse, comprising central Pleural effusion 25
and peripheral nervous system manifestations and focal to more Pulmonary hypertension 0.5e20
diffuse syndromes. This diversity results in diagnostic difficulty, Pericarditis 15
particularly because this can be present without abnormalities in Myocarditis <15
the typical markers of active lupus such as anti-dsDNA and Conduction disturbance 10
complement. Disruption of the bloodebrain barrier has been Interstitial alveolitis/pneumonitis 1e12
thought to be important for the development of neuropsychiatric Interstitial fibrosis 3e13
SLE. Headaches are a common neurological complaint in SLE Shrinking lung syndrome <1
patients but are not specific or linked to active disease. However, Coronary vasculitis rare
it is important to assess for the presence of red flag signs sug- Gastrointestinal
gesting a subarachnoid haemorrhage, venous sinus thrombosis Abdominal pain 8e40
and meningitis. Reduction in cognitive function, ‘brain fog’ and Nausea 15
depression are other common complaints. Intestinal vasculitis 0.2e14
Gastrointestinal symptoms are common in SLE, but are usually Vomiting <10
mild and related to infective causes or are an adverse effect of Diarrhoea <10
treatment for SLE. Gastrointestinal manifestations of SLE, which Lupus hepatitis 9
can result from gut vasculitis, can result in increased morbidity if Lupus pancreatitis <4
not identified and treated. Lupus enteritis is a potentially fatal Lupus peritonitis/abdominal serositis Rare
gastrointestinal manifestation, with symptoms varying from those Acute lupus cholecystitis Rare
of an acute abdomen to pseudo-obstruction or protein-losing en- Renal
teropathy.3 Associations between SLE and autoimmune gastro- Proteinuria 60
intestinal diseases are rarely reported. Alves et al.’s review (see Casts 30
Further reading) reported that inflammatory bowel disease can Haematuria 10
present before or after the diagnosis of SLE, with a prevalence for Neuropsychiatric
ulcerative colitis of 0.4e0.7%, and for Crohn’s disease of <0.4%. Central nervous system
Primary biliary cirrhosis occurs in 0.3e2.4% of patients with SLE. Cognitive dysfunction 27e80
Autoimmune hepatitis has been reported in 3e10% of patients Headache (migraine, benign intracranial 21e50
with SLE, with a higher incidence in patients with juvenile SLE. hypertension)
Other autoimmune diseases can coexist with SLE; these include Anxiety 20
secondary Sjo €gren’s syndrome, overlap syndromes with features Seizures 20
of rheumatoid arthritis and scleroderma, hypothyroidism and Depression 15
antiphospholipid syndrome. Cerebrovascular disease 15
The prognosis of SLE has markedly improved in the last 50 Hemiplegia 10
years, with a current 5-year survival rate of >90%. This is mainly Cranial nerve lesions 10
due to the result of advances in immunosuppressive therapy,
dialysis and transplantation, and in general management, (continued on next page)

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 SYSTEMIC LUPUS ERYTHEMATOSUS

more likely to develop haematological malignancies, in partic-

Table 3 (continued )
ular, non-Hodgkin’s lymphoma and leukaemia, and there is also
Clinical feature Prevalence (%) a small increased risk of lung, thyroid and vulval cancers. The
pre-cancerous stage, cervical dysplasia, has been reported to
Psychosis 10 have a higher incidence in patients with SLE, especially in those
Acute confusional state <10 who have been treated with cyclophosphamide. This highlights
Cerebellar ataxia 5 the importance of SLE patients adhering to national cervical
Myelopathy 1e3 screening programmes. Interestingly, there is a lower risk of
Aseptic meningitis 0.4e3 developing breast, endometrial and ovarian cancers in women,
Demyelinating syndrome 0.2e2 and prostate cancers in men.
Chorea/movement disorder 1 Pregnancy morbidity is higher in patients with SLE and in-
Peripheral nervous system cludes miscarriages, intrauterine growth restriction and pre-term
Polyneuropathy 2.8e28 birth; the presence of LN and antiphospholipid syndrome further
Cranial neuropathy 1.5e7 increase this risk. The risk of neonatal heart block is estimated to
Mononeuropathy 1e7 be 2% with anti-Ro antibody-positive mothers, increasing further
Myasthenia gravis 0.2e2 to 15% in the next pregnancy if neonatal heart block was present
Acute inflammatory demyelinating <1 in the previous pregnancy. Good control of the SLE for at least 4
polyradiculopathy months before conception optimizes pregnancy outcomes.3
Haematological Susceptibility to infections, the most common being respira-
Anaemia tory tract infections, has been thought to be the result of an
Chronic disease 75 impaired immune response. This susceptibility is further com-
Iron deficiency 30 pounded by increased lupus activity, hypocomplementaemia,
Autoimmune haemolytic 3e15 leucopenia, corticosteroid use (7.5 mg/day) and immunosup-
Lymphopenia 75 pressants such as cyclophosphamide. The mortality rate from
Leucopenia 30e60 infections in patients with SLE has been reported to be nearly five
Thrombocytopenia 15e25 times that of the general population. In contrast, hydroxy-
Ophthalmic chloroquine may have a protective effect against infection.
Retinal disease 3e29 It is important to review the vaccination status in patients
Keratoconjuncivitis sicca 25 with SLE. In general, ‘live’ vaccinations for patients on immu-
Anterior/posterior uveitis 0.1e4.8 nosuppressants or >10 mg of prednisolone should be avoided.
Optic neuropathy: neuritis, ischaemic 1 However, non-live vaccinations have been thought to be safe in
neuropathy, papilloedemia SLE patients taking immunosuppressive drugs. It is advised that
Orbital inflammation, myositis, proptosis n/a patients with SLE are given the appropriate immunizations,
Keratitis n/a especially against pneumococcus, and the yearly influenza vac-
Episcleritis/scleritis n/a cine. In addition, in certain age groups, immunizations as per
n/a; not available. national vaccination schedules, such as the human papilloma-
Adapted from Morrow, J. et al.. Systemic lupus erythematosus. In: Autoimmune virus and meningococcus ACWY vaccination, should be given.
Rheumatic Disease. 2nd ed. Oxford University Press. 1999. 4:p. 59.
Indices
Table 3 Since the 1980s, new tools have been created to capture disease
activity (as a global or individual organ/system score), damage
including antihypertensive drugs and statins. In addition, the and quality of life in patients with SLE. Standard measures of
recognition and management of co-morbidities, such as osteo- these aspects are critical when comparing different groups of
porosis and cardiovascular disease, have improved. However, patients and assessing the response to drugs. The correlation
the mortality rate is still increased compared to the general between indices measuring different aspects of the disease is
population, with a recent meta-analysis reporting all-cause poor, suggesting that they are complementary and should all be
mortality to be 2.6 times that of the general population. In the measured. The two most popular indices capturing disease ac-
last 40 years, it has been recognized that cardiovascular disease tivity are the British Isles Lupus Assessment Group (BILAG)
is a major cause of death in SLE, particularly later in the course of index and the Systemic Lupus Erythematosus Disease Activity
the disease. Index (SLEDAI).5
Classical cardiovascular risk factors contribute to this
increased risk, notably smoking (20% of patients in most cohorts Treatment
continue to smoke), hypertension and dyslipidaemia. In addi- The treatment of SLE depends on the organ and systems involved
tion, the sustained inflammation in autoimmune diseases leads and the severity of disease, and can vary from topical medicines
to accelerated atherosclerosis. Thromboembolic events are also for skin disease and non-steroidal anti-inflammatory diseases for
more common in SLE. musculoskeletal disease to aggressive systemic immunosup-
Patients with SLE have been found to have an increased risk pression. It is now clear that associated diseases such as osteo-
of certain malignancies. In a large multicentre international study porosis and cardiovascular disease should be prevented and
by Bernatsky et al. SLE patients were found to be three times diagnosed and treated early. Osteoporosis is strongly associated

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 SYSTEMIC LUPUS ERYTHEMATOSUS

with SLE, and the World Health Organization suggests regular National Institutes of Health (NIH) studies in the 1980s
dual X-ray absorptiometry for a correct diagnosis of osteoporosis, established that cyclophosphamide-containing regimens were
to determine the fracture risk and monitor the effect of treatment. more effective than corticosteroids alone when treating LN.
Patients with SLE should also be screened for the presence of Importantly, in 2002, the Euro-Lupus Nephritis trial demon-
cardiovascular risk factors and cardiovascular disease. Modifiable strated that a low-dose cyclophosphamide regimen was as
risk-factors such as hypertension and hyperlipidaemia should be effective as the high-dose NIH regimens and had fewer (although
identified and concurrently managed. The importance of smoking not statistically significant) adverse effects. The Euro-Lupus
cessation should be emphasized for reduction of cardiovascular regime is currently the preferred cyclophosphamide regimen
risk and may improve cutaneous lupus. Angiotensin-converting- but, because cyclophosphamide is very toxic even in low-dose
enzyme (ACE) inhibitors should be considered, not only for regimens and because a significant percentage of patients are
blood pressure control (aiming for a diastolic blood pressure of still resistant, new drugs have been tested.
<80 mmHg), but also to reduce the level of proteinuria in patients The Aspreva Lupus Management Study (ALMS) trial showed
with LN and progression towards end-stage renal disease. that MMF is a good option for the induction phase because it is as
SLE patients, especially those with cutaneous manifestations, effective as cyclophosphamide. It also has fewer adverse effects
should be advised to reduce exposure to strong sunlight and to than cyclophosphamide and is more effective than azathioprine.
use adequate sun protection (SPF 50þ). Importantly, cyclophosphamide and MMF are contraindicated in
pregnancy and breastfeeding, and therefore azathioprine,
Corticosteroids although inferior to MMF, is preferred during pregnancy and
Corticosteroids modify genomic and non-genomic pathways, the fertility preservation.
latter being activated at higher dosages (prednisolone >30 mg/ Cyclophosphamide has been used to treat myositis and gastro-
day), leading to immunosuppressive and anti-inflammatory ef- intestinal and pulmonary manifestations. MMF is also effective in
fects. The dose and route of administration of these drugs varies refractory haematological and dermatological manifestations. In
according to the organ(s) affected and the severity of the disease; the ALMS trial, it was shown that cyclophosphamide and MMF are
there are no guidelines describing the ideal regimen. In mild dis- similarly effective in controlling extra-renal disease in patients with
ease, there is usually a response to prednisolone 5e15 mg/day or renal lupus. For neuropsychiatric lupus, there is a lack of evidence
equivalent, and a sparing agent or antimalarial can also be used. In concerning the best treatment option, but corticosteroids alone or
life-threatening and organ-threatening disease, methylpredniso- in combination with cyclophosphamide or azathioprine are rec-
lone is used as a pulsed intravenous therapy. Some patients do not ommended; other drugs are used in refractory cases.
respond sufficiently to corticosteroid agents, and in some mani- Both tacrolimus and ciclosporin, via inhibition of calcineurin,
festations of SLE, a combination with an immunosuppressive drug inhibit the production of cytokines and lymphocyte proliferation,
is more effective. Close monitoring for adverse effects, especially especially of T helper cells. There is some evidence that tacroli-
with high doses of corticosteroids, is mandatory. mus is effective in induction treatment for LN. Ciclosporin can be
used as a corticosteroid-sparing drug in patients with normal
Hydroxychloroquine renal function.
The immunomodulatory properties of this drug mean it can be
used to: treat articular and skin flares; protect against the effects Biological therapy3
of ultraviolet light; improve sicca symptoms; treat milder disease; To date, the most logical and widely used biological option in
and give a more favourable cardiovascular profile in different SLE has been B cell depletion achieved by direct B cell elimina-
ways (reducing cholesterol, risk of diabetes mellitus and risk of tion or inhibition of B cell survival agents.
development of carotid plaque, and having antithrombotic
properties). Belimumab is a human monoclonal IgG1 that binds to BLyS (also
In patients with renal disease, it also facilitates the response to known as BAFF, B cell activating factor), an important B cell
mycophenolate mofetil (MMF), and ACR’s 2012 guidelines sug- stimulator protein. In March 2011, belimumab became the first
gest that it should be given to every lupus patient with nephritis. drug in 50 years to be approved by the Food and Drug Adminis-
It was also shown that it prevents damage in the kidneys and tration for the treatment of SLE, and it has subsequently obtained
central nervous system and, probably as a result of all of this, National Institute for Health and Care Excellence approval. The
reduces mortality. Although hydroxychloroquine is generally a BLISS-76 and BLISS-52 clinical trials showed belimumab’s efficacy
safe drug, prescribers should be aware of the rare adverse effect in reducing disease activity and preventing flares; this was partic-
of ocular toxicity and initiate appropriate ophthalmology sur- ularly shown for mucocutaneous and musculoskeletal manifesta-
veillance for this. Our practice is to seek a detailed ophthal- tions and in a subset of autoantibody-positive patients (ANA titre
mology review after 5 years on the drug (200e400 mg/day, 1:80 and/or anti-dsDNA antibody concentration 30 IU/ml) with
roughly 6.5 mg/kg per day). Cardiotoxicity is a serious but very a low C3 concentration. It has not yet been established whether it is
rare adverse effect, described in case reports. effective in LN and central nervous system manifestations.

Immunosuppressives3 Rituximab is a chimeric mouse/human monoclonal antibody

Other immunosuppressive drugs are used in severe manifesta- against CD20 on the surface of pre-B cells maturing to memory B
tions of SLE. LN is the most common life-threatening manifes- cells. The binding triggers apoptosis of peripheral B cells without
tation and has been the working field for research into the effects avoiding the regeneration from stem cells. It is licensed for non-
of new drugs. Hodgkin’s lymphoma, chronic lymphocytic leukaemia,

MEDICINE --:- 7 Ó 2017 Published by Elsevier Ltd.

Please cite this article in press as: Yeoh SA, et al., Advances in systemic lupus erythematosus, Medicine (2017), https://doi.org/10.1016/
j.mpmed.2017.11.010
 SYSTEMIC LUPUS ERYTHEMATOSUS

rheumatoid arthritis and granulomatosis with polyangiitis. In the Remission

UK, rituximab is currently widely used off-licence to treat SLE, The international initiative treat-to-target for SLE was established
funded by NHS England. to provide recommendations to treat according to a target iden-
In many open-label studies, rituximab has shown efficacy in tified for each patient. ‘Remission of systemic symptoms and
treating different features, such as fatigue, skin, arthritis, seros- organ manifestations’ was named as one of the targets. Treat-
itis and renal disease, in SLE. It is safe and well tolerated when ment of SLE can be aimed to treat active disease, towards a lupus
used either alone or in combination or with cyclophosphamide. low disease activity state to remission with treatment, with the
Rituximab’s corticosteroid-sparing effect is of great impor- ultimate aim of remission off treatment.
tance. A study of 50 LN patients, at the time of diagnosis (and Studies on remission in SLE have used various definitions of
before oral steroids were given), who were treated with the remission, including absence of clinical and serological activity,
RITUXILUP (steroid-avoiding) protocol using rituximab and serological activity but clinically quiescent, and whether these
MMF, also demonstrated efficacy despite the lack of concomitant states are achieved on or off treatment. A UK study by Medina
oral corticosteroids. Quinones et al., (see Further reading) reported complete disease
Disappointingly, two randomized controlled studies, EX- remission of at least 3 years in 14.5% of patients, while another
PLORER and LUNAR, failed to show benefit from adding ritux- study by Zen et al. (see Further reading) reported prolonged
imab to continuing immunosuppressive treatment in patients disease remission of at least 5 years in 37%. A recent study by
with extra-renal and renal lupus, respectively. Inadequate trial Wilhelm et al. (see Further reading) however, reported durable
design almost certainly played a part, as patients with severe and disease remission to be a rare entity in SLE. They reported me-
refractory disease were excluded and a high dose of corticoste- dians of 1.8 and 3.1 years, respectively, to achieve clinical and
roids was maintained, obscuring the efficacy of rituximab and its complete remission on treatment, and 8.7 and 11.0 years,
corticosteroid-sparing effect. respectively, to achieve clinical and complete remission. In this
study, patients of African-American origin and baseline C3 and
Ofatumumab, a fully humanized monoclonal antibody against C4 hypocomplementaemia were found to be associated with a
CD20 antigen, which is licensed in the UK to treat chronic lym- longer period of time to remission.
phocytic leukaemia, has been demonstrated in case studies to be Because of the lack of a consensus on the definition of
effective in treating SLE. This is a promising option for off-licence remission, a large international task force on Definitions of
use in cases where rituximab is not tolerated. Remission in SLE (DORIS) have published eight key statements
and three principles for defining remission to try to harmonize
research efforts. The presence or absence of treatment has to be
Atacicept (which blocks the B cell activating factors BLyS and
distinguished when defining remission. Remission in SLE re-
APRIL) has shown promising results in both flare-prevention and
mains a controversial topic, but there is evidence of improved
active disease trials. In the APRIL-SLE Phase II/III trial, atacicept
outcomes and reduced damage accrual in patients with pro-
150 mg was shown to be associated with a reduced flare rate.
longed remission and lupus low disease activity state. A
Unfortunately, two fatal pulmonary infections led to the prema-
ture termination of the atacicept group in the trial (deaths in
small numbers of SLE patients have been reported in every SLE KEY REFERENCES
trial). Subsequently, the ADDRESS II trial, comparing atacicept 1 Lewis MJ, Jawad AS. The effect of ethnicity and genetic ancestry
75 mg and 150 mg with placebo in treating moderately active on the epidemiology, clinical features and outcome of systemic
SLE, has shown atacicept to be efficacious at reducing disease lupus erythematosus. Rheumatol Oxf 2017; 56(suppl 1): i66e77.
activity as well as in flare prevention, with no increase in the risk 2 Gatto M, Zen M, Ghiradello A, et al. Emerging and critical issues in
of serious adverse events. the pathogenesis of lupus. Autoimmun Rev 2013 Feb; 12(4):
Anifrolumab, rontalizumab and sifalizumab are IFNa-block- 523e36.
ing agents. A Phase II trial involving rontalizumab did not meet 3 Gordon C, Isenberg D(eds). Systemic lupus erythematosus. Oxford
its primary outcome. Sifalizumab and anifrolumab have shown Medical Libraries, Oxford Rheumatology Library. Oxford: Oxford
promising results in preliminary trials, especially in patients with University Press, 2016.
a high IFNa signature. 4 Petri M, Orbai AM, Alarco  n GS, et al. Derivation and validation of
A variety of other monoclonal antibodies including TNFa the systemic lupus international collaborating clinics classification
blockers, the IL-6 receptor blocker tocilizumab and abatacept criteria for systemic lupus erythematosus. Arthritis Rheum 2012;
(which blocks the links between antigen-presenting cells and T 64: 2677e86.
cells) have also been used in relatively small numbers of patients 5 Romero-Diaz J, Isenberg D, Ramsey-Goldman R. Measures of adult
with variable benefit. Eculizumab, a fully humanized IgG2/IgG4 systemic lupus erythematosus: updated version of British Isles lupus
monoclonal antibody against C5 has also undergone Phase I trial. assessment group (BILAG 2004), European consensus lupus activity
No biological drug apart from belimumab has been approved in measurements (ECLAM), systemic lupus activity measure, revised
the UK for the treatment of SLE, and further data are needed to (SLAM-R), systemic lupus activity questionnaire for population
support their use. Many other approaches are at phase II or phase studies (SLAQ), systemic lupus erythematosus disease activity index
III stages at present, including attempts to block the Fc Gamma II 2000 (SLEDAI-2K), and systemic lupus international collaborating
receptor and the CD40 ligand, but these approaches are not yet clinics/American College of Rheumatology damage index (SDI).
approved for lupus. Arthritis Care Res (Hoboken) 2011; 63(suppl 11): S37e46.

MEDICINE --:- 8 Ó 2017 Published by Elsevier Ltd.

Please cite this article in press as: Yeoh SA, et al., Advances in systemic lupus erythematosus, Medicine (2017), https://doi.org/10.1016/
j.mpmed.2017.11.010
 SYSTEMIC LUPUS ERYTHEMATOSUS

FURTHER READING Medina-Quin ~ones CV, Ramos-Merino L, Ruiz-Sada P, et al. Analysis of

Alves SC, Fasano S, Isenberg DA. Autoimmune gastrointestinal complete remission in systemic lupus erythematosus patients over
complications in patients with systemic lupus erythematosus: a 32-year-period. Arthritis Care Res (Hoboken) 2016; 68(7): 981e7.
case series and literature review. Lupus 2016; 25(14): Zen M, Iaccarino L, Gatto M, et al. Prolonged remission in Caucasian
1509e19. patients with SLE: prevalence and outcomes. Ann Rheum Dis
Bernatsky S, Boivin JF, Joseph L, et al. An international cohort study 2015; 74(12): 2117e22.
of cancer in systemic lupus erythematosus. Arthritis Rheum 2005; Wilhelm TR, Magder LS, Petri M. Remission in systemic lupus erythema-
52(5): 1481e90. tosus: durable remission is rare. Ann Rheum Dis 2017; 76(3): 547e53.

TEST YOURSELF
To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the
end of the issue or online here.

Question 1 What investigation would be most appropriate in identifying

the cause of the abnormal urine dipstick result in this patient?
A 30-year-old woman consulted to discuss plans about starting a
A. Renal ultrasound
family. She had a history of systemic lupus erythematosus with
B. Blood test for anti-double-stranded DNA and complement
previous lupus nephritis and extra-renal flares requiring cyclo-
levels
phosphamide. Her disease had been stable for the previous 6
C. Renal biopsy
months on hydroxychloroquine 400 mg daily and mycophenolate
D. Urine protein:creatinine ratio and microscopy for casts
mofetil (MMF) 750 mg twice daily.
E. CT of the kidney/ureter/bladder
What is the best advice regarding her current medication
regimen? Question 3
A. Advise no change to her current medication
A 30-year-old man presented with joint pain, fatigue and mouth
B. Stop hydroxychloroquine and MMF
ulcers. He also had a facial rash made worse by sunlight. Four
C. Continue hydroxychloroquine and replace MMF with
years previously, he had been found to have Crohn’s disease,
prednisolone
which had been complicated by fistula formation. He had been
D. Continue hydroxychloroquine and replace MMF with
treated with a tumour necrosis factor-blocking drug, infliximab,
azathioprine
for the previous 6 months.
E. Continue hydroxychloroquine monotherapy
Investigations
Question 2  Antinuclear antibodies 1:640 (previously negative)
 Autoantibody screen negative
A 40-year-old woman presented for review. A year previously,
 Serum complement levels normal
she had been found to have systemic lupus erythematosus, with
a rash and arthralgia that had improved with treatment, but her
fatigue had persisted. She also had type II diabetes mellitus and What is the most likely diagnosis?
hypertension. She was taking hydroxychloroquine, metformin A. Treatment failure of infliximab
and amlodipine. B. Allergic reaction to infliximab
On clinical examination, her blood pressure was 145/98 mmHg. C. Drug-induced lupus
Urine dipstick testing showed 3þ protein and a trace of blood. D. Systemic lupus erythematosus
E. Crohn’s-related arthritis
Investigations
 Serum urea 6.5 mmol/litre (2.5e7.0)
 Serum creatinine 100 micromol/litre (60e110)

MEDICINE --:- 9 Ó 2017 Published by Elsevier Ltd.

Please cite this article in press as: Yeoh SA, et al., Advances in systemic lupus erythematosus, Medicine (2017), https://doi.org/10.1016/
j.mpmed.2017.11.010