Download - Systemic lupus erythematosus
SLE
Systemiclupus erythematosusCaroline Gordon
Charles K Li
David A Isenberg
AbstractSystemic lupus erythematosus (SLE) is a diverse auto-immune rheumatic
disease principally affecting women during childbearing years. The
female-to-male ratio is about 9:1. Although virtually all patients have
skin and joint disease, between 30 and 50% will also develop renal,
lung, heart and central nervous system involvement. SLE has a prevalence
of approximately 20e200 per 100,000, occurring most commonly in the
Afro-Caribbean population. Its diversity of clinical features is, apparently,
matched by the wide range of associated autoantibodies. Antibodies to
double-stranded DNA (dsDNA), single-stranded DNA (ssDNA), nucleo-
somes, C1q, Ro and RNP are found most commonly. Autoantibodies to
dsDNA and nucleosomes are useful diagnostically and probably
contribute to the pathogenesis of the disease. Its pathogenesis is
a complex combination of hormonal, genetic and trigger factors (infec-
tion, ultraviolet radiation). The prognosis has improved in the past 50
years from 50% 4-year survival to around 85% 10-year survival. This
improvement has been brought about in part by optimizing the use of
hydroxychloroquine, corticosteroids and immunosuppressives (azathio-
prine, cyclophosphamide and more recently mycophenolate). With an
increased knowledge of the factors involved in pathogenesis, some
exciting new modes of treatment (e.g. B cell depletion, anti-B cell stimu-
lating factors) are entering clinical trials with the hope of further
improving mortality and morbidity.
Keywords B cell depletion; dsDNA autoantibody; mycophenolate;
systemic lupus erythematosus; UV light
Systemic lupus erythematosus (SLE) is a multi-system auto-
immune disease with protean clinical manifestations that may
affect any organ or system. Table 1 shows the 1997 revised
American College of Rheumatology (ACR) criteria for the clas-
sification of SLE. The disease is characterized by flares, remis-
sions and autoantibodies directed against several intracellular
Caroline Gordon MD FRCP is Professor of Rheumatology at the University
of Birmingham and associated hospitals, UK. Competing interests:
none declared.
Charles K Li PhD MRCP is Consultant Rheumatologist in the Department
of Rheumatology at Hammersmith Hospital, London, UK. Competing
interests: none declared.
David A Isenberg MD FRCP FAMS is Arthritis Research Campaign Professor
of Rheumatology at University College London, UK. Competing
interests: none declared.
MEDICINE 38:2 73
and cell-surface antigens. The course of the disease is variable
and regular review is essential to detect new and recurrent
organ/system involvement. However, not all of the antibodies
found in SLE are clinically relevant. Table 2 shows the preva-
lence of autoantibodies in 500 patients attending the University
College Hospital/Middlesex Hospital Lupus Clinic between 1978
and 2008.
Patients with SLE are now living longer as a result of more
appropriate use of ‘standard drugs’, such as hydroxychloroquine,
prednisolone, azathioprine and cyclophosphamide, and adjunc-
tive therapies, such as antihypertensives and cholesterol-
lowering drugs. The use of dialysis and renal transplantation has
also improved survival, and new immunotherapies are under
development. Management of a patient with SLE rigorously tests
the clinician’s skills and judgement as it can be difficult to
distinguish features of active lupus from complications such as
infection and co-morbid conditions such as malignancy. Such
patients are best cared for by experienced physicians with
support from a multidisciplinary team.
Epidemiology
SLE is found worldwide, with an estimated prevalence of 22e241/
100,000population. In theUK, theCaribbeanand theUSA, it ismore
common and more severe in females of African descent than in
white Caucasians. In a study in Birmingham, UK, the estimated
prevalence in adult women was 206/100,000 in Afro-Caribbeans,
95/100,000 in South Asians and 36/100,000 in Europeans. The
incidence is higher in urban populations. In most patients, SLE
develops between the agesof 15and 50years. The female:male ratio
is at least 9:1. Ina minorityofpatients, diseasedevelopsafter theage
of 50 years, and in this subgroup the female:male ratio is 4:1. In
childhood disease, the ratio of girls to boys is 3:1.
Aetiology
The precise aetiology of SLE is unknown. It is hypothesized that,
like most systemic auto-immune conditions, SLE is triggered by
one or a series of external stimuli in a genetically susceptible
individual. The highly skewed sex differences and the age of
onset in females point to a strong hormonal influence.
Genetic factors
Studies in monozygotic twins have found a concordance of
23e57%. Concordance in dizygotic twins is no greater than that
in first-degree relatives (generally estimated at 3e5%). Family
studies have shown that the prevalence of definite SLE in first-
degree relatives of index patients is about 10 times that in control
groups. In a cohort of 300 patients in London, UK, 24 patients
(8%) had at least one first-degree relative with SLE and 20e30%
had a first-degree relative with another auto-immune disease.
Many studies have attempted to identify candidate genes in
SLE, but often the implicated genes have not been confirmed and
remain controversial. Current evidence suggests a role for the
human leukocyte antigen (HLA) region, complement compo-
nents, immunoglobulin G (IgG) receptors and the cytokine
interferon-alpha.
� The HLA alleles A1, B8, DR2 and DR3 have shown associa-
tions with SLE in Caucasian populations. HLA associations in
non-Caucasian populations have been less convincing.
� 2009 Elsevier Ltd. All rights reserved.
1997 update of 1982 American College ofRheumatology classification criteria for systemiclupus erythematosus
C Malar rash
C Discoid rash
C Photosensitivity
C Oral ulcers
C Non-erosive arthritis
C Pleuritis or pericarditis
C Renal disorder
Persistent proteinuria > 0.5 g/day or 3þ if not quantified
Cellular casts
C Neurological disorder
Seizures in absence of known metabolic derangements or
offending drugs
Psychosis in absence of metabolic derangements or offending
drugs
C Haematological disorder
Haemolytic anaemia
Leucopenia
Lymphopenia
Thrombocytopenia
C Immunological disorder
Abnormal anti-DNA titre
Anti-Sm antibody
Antiphospholipid antibodies
C Positive antinuclear antibody
Systemic lupus erythematosus is diagnosed when four of the 11 criteria are
documented at any time in the history.
Table 1
Autoantibody profile of 500 patients attending theUniversity College Hospital/Middlesex Hospital LupusClinic between 1978 and 2008
Antibody Patients (%)
Antinuclear antibody > 1/80 95
Anti-Sm 13
Anti-RNP 27
Anti-Ro 37
Anti-La 13
Anti-dsDNA 64
Low complement C3 44
Rheumatoid factor 25
Anticardiolipin (IgG) 21
Anticardiolipin (IgM) 9
Lupus anticoagulant 14
Coombs’-positive 25
Antithyroglobulin 13.5
Antithyroid microsomal 12.5
dsDNA, double-stranded DNA; IgG, immunoglobulin G; IgM, immunoglobulin
M; RNP, ribonucleoprotein.
Table 2
SLE
� Deficiencies in classical pathway complement components
C1q, C2 and C4 are strongly associated with the development
of a lupus-like disease.
� IgG receptors on mononuclear phagocyte cells clear IgG and
IgG-containing immune complexes from the circulation. In
Afro-American patients, associations have been found
between SLE and the presence of low-affinity IgG receptors.
� Other genetic factors include cytotoxic T lymphocyte antigen
4 (CTLA4), a negative regulator of T cells, programmed cell-
death-1 (PBCD-1), an immunoreceptor of the CD28 family,
and cytokines such as interferon-alpha (IFN-a) and tumour
necrosis factor-alpha (TNF-a).
Hormonal and environmental influences
SLE and other auto-immune diseases, such as Sjogren’s
syndrome and rheumatoid arthritis, are more common in
women. In certain mouse models of SLE, androgen administra-
tion suppressed disease in both sexes, whereas administration of
oestrogen or progesterone accelerated disease and increased
mortality in both sexes. In humans, some case reports and
prospective studies have linked the oral contraceptive pill with
the onset of SLE.1 Results have been variable in retrospective
studies of the effect of the oral contraceptive pill on disease
activity. In the prospective Nurses’ Health Study, the risk of SLE
MEDICINE 38:2 74
was greater in nurses taking hormone replacement therapy
(HRT)2 and a large randomized prospective study has shown that
a short course of HRT may increase the risk of a lupus flare.
These results would seem to parallel the findings in the Women’s
Health Initiative Trial in 2002, which raised concerns about the
use of hormone replacement in post-menopausal SLE patients. In
contrast, various caseecontrol studies have failed to show an
association between oral contraceptive use and serious disease
flare in SLE patients.
Drugs such as minocycline, procainamide, hydralazine and
penicillamine can also induce a lupus-like syndrome in suscep-
tible individuals. Ultra-violet light can exacerbate cutaneous and
systemic disease in SLE patients.
Pathogenesis
There is evidence that anti-double-stranded DNA (dsDNA) anti-
bodies are directly pathogenic and related to disease activity.
Circulating immune complexes are an immunopathological
hallmark of SLE. They can deposit or be formed in the skin,
kidney and brain, thereby initiating an inflammatory reaction,
and clearance of these complexes may be impaired in SLE
patients. Immune complexes also activate complement
consumption. Certain complement fragments (e.g. C3a) cause
the release of pro-inflammatory cytokines or increase vascular
permeability. Other abnormalities include increased numbers of
activated B lymphocytes and defects in T cell responses.
Apoptosis, or programmed cell death, results in the involution
of a cell with its nuclear components appearing on the cell
surface. Apoptotic cells are usually removed very efficiently by
macrophages. Deficient clearance of apoptotic cells linked to
macrophage malfunction and/or conditions of stress such as
infection and exposure to ultraviolet light can generate large
� 2009 Elsevier Ltd. All rights reserved.
SLE
amounts of antigen to which the immune system may not be
tolerant. This has led to an intriguing but attractive hypothesis
that can explain both the trigger and the continuous drive of the
disease process.3
Clinical features
Non-specific features
Patients can present with fever, fatigue, anorexia, weight loss
and/or lymphadenopathy, and often need to undergo a series of
investigations, including biopsy, to exclude malignancy or
infection, such as tuberculosis. Fever is associated with active
disease and must be differentiated from infection. SLE patients
are immunosuppressed as a result of the disease and its treat-
ment. C-reactive protein (CRP) is usually not raised in active SLE
(except in serositis and arthritis). If CRP is found to be elevated,
a careful search should be made for a source of infection. Fatigue
is very common and debilitating, is usually multifactorial in
origin and is difficult to treat.
Musculoskeletal features
Joint pain with early morning stiffness (arthralgia) is present in
most SLE patients. It is symmetrical, flitting and usually poly-
articular. Frank synovitis and joint effusions are rare. Erosive
arthropathy occurs in about 5% of patients. Non-erosive,
deforming Jaccoud’s arthropathy associated with ligamentous
laxity is more common; this is often reversible and less painful
than it appears. Muscle pain (myalgia) is also common, but
inflammatory myositis occurs in only a few patients (5e10%).
Avascular necrosis of bone causes major morbidity in SLE. It
is associated with active disease and corticosteroid use. Predic-
tive factors for development of avascular necrosis are thought to
be severe active disease, cushingoid habitus, and prednisone
dose, but not the presence of antiphospholipid antibodies. The
hip, knee, wrist or ankle can be affected.
Osteoporosis is an important complication of SLE. It can result
from lack of vitamin D caused by sun avoidance, menstrual cycle
dysfunction from disease or treatment, corticosteroid use or lack
of exercise. In at-risk patients, bone density should be measured
every 1e2 years and prophylactic treatment commenced if
necessary.
Cardiovascular features
Symptomatic pericarditis occurs at some time in about 25% of
SLE patients, but is probably much more common in subclinical
forms. The symptoms are those of pericarditis in general. Signs
include fever, tachycardia and reduced heart sounds (if a peri-
cardial effusion is present) and/or pericardial rub. Cardiac tam-
ponade is rare.
Conduction abnormalities may not be caused by SLE per se.
Their presence often reflects ischaemic heart disease. Congenital
heart block occurs in about 2% of children born to mothers with
anti-Ro or anti-La antibodies.
True immune-mediated myocarditis is rare. Symptoms
include fever, dyspnoea, tachycardia and other features of heart
failure. The diagnosis is difficult to prove and only a biopsy can
confirm it. Most cases of myocardial dysfunction in SLE are
caused by ischaemic heart disease or hypertension. Similarly,
acute coronary vasculitis is rare. It is increasingly recognized that
persistent disease activity is associated with accelerated
MEDICINE 38:2 75
atherosclerosis in chronic inflammatory rheumatic diseases such
as rheumatoid arthritis and SLE.4 However, both traditional risk
factors in the development of cardiovascular disease (hyper-
lipidaemia, hyperhomocysteinaemia, hypertension and diabetes,
the latter two linked with corticosteroid use) and SLE disease-
related risk factors (antiphospholipid antibodies, anti-oxidized
low density lipoprotein (oxLDL) antibodies, deficiency of the
paraoxonase enzyme which regulates the oxygenation of lipo-
proteins and inflammatory mediators) have been implicated. It is
thought that antiphospholipid antibodies can bind to oxLDL and
b2-glycoprotein complexed with oxLDL, resulting in accelerated
formation of atheromatous plaques.
The incidence of myocardial infarction and carotid artery
stenosis in female SLE patients aged 35e44 years is shown to be
50 times that in controls in the Framingham Offspring Study. It is
therefore vital to screen for and minimize cardiovascular risk
factors by treating hypertension and hyperlipidaemia, reducing
corticosteroids to the lowest dose possible for control of disease,
and encouraging cessation of smoking. Extensive studies have
been done on the use of HRT in post-menopausal SLE patients,
and it is now thought that this is relatively safe for short-term
use, providing that the patient is not at increased risk of throm-
bosis. The use of immunomodulatory drugs to lower disease
activity is correlated with lower rates of atherosclerotic disease.
Pulmonary features
Pleuritic chest pain occurs in 45e60% of patients, with or
without pleural effusion. Effusions can be unilateral or bilateral.
Acute pneumonitis is rare and can be fatal. Chronic interstitial
pneumonitis can be severe but is uncommon. Acute alveolar
haemorrhage is also rare but has a high mortality. Pulmonary
hypertension in SLE may result from multiple factors such as
vasculitis, thrombosis and pulmonary artery vasoconstriction.
The prognosis is poor. Thromboembolic disease is associated
with the presence of the lupus anticoagulant and anti-
phospholipid antibodies. Such patients may need lifelong anti-
coagulation. SLE patients are at higher risk of pulmonary
infections because of immunosuppression. It is important to
exclude infection in patients with new chest radiograph changes.
‘Shrinking lung syndrome’ is characterized by dyspnoea (may
be progressive), diaphragmatic weakness and the radiological
finding of small lung volumes. Symptoms have been improved
by corticosteroids, theophylline and inhaled beta-agonists.
Gastrointestinal features
Symptoms are common in SLE.5 Anorexia, nausea and vomiting
occur in up to 50% of patients, but may be caused by medication
or other problems such as uraemia. Oral lesions (classified as
discoid, erythematosus or ulcerative) occur in 7e52% of
patients. Sjogren’s syndrome can co-exist with SLE and can cause
gingivitis, accelerated dental caries and oral infections such as
candidiasis. SLE patients are at risk of peptic ulcer disease from
the use of non-steroidal anti-inflammatory drugs (NSAIDs) and
corticosteroids; a gastroprotective agent may be helpful.
Potentially serious complications of SLE occur in the large and
small intestine secondary to small vessel vasculitis. This can lead
to bowel ischaemia and infarction with resultant bleeding,
perforation or peritonitis. Abdominal pain occurs in 8e40% of
patients, but it is important to remember that there are many
� 2009 Elsevier Ltd. All rights reserved.
Classification of renal lupus
WHO 1995 classification ISN/RPS 2003 classification
I Normal glomeruli I Minimal mesangial lupus nephritis
II Mesangiopathy II Mesangial proliferative lupus nephritis
III Focal segmental
glomerulonephritis
III Focal lupus nephritis
III(A) active lesions
III(A/C) active and chronic lesions
III(C) chronic lesions
IV Diffuse
glomerulonephritis
IV Diffuse lupus nephritis
IV-S(A) active lesions: diffuse segmental
IV-G(A) active lesions: diffuse global
IV-S(A/C) active and chronic lesions:
SLE
other causes of abdominal pain. Gastrointestinal vasculitis is
almost always accompanied by other evidence of disease
activity. Symptoms and signs range from pain, nausea and
vomiting to massive gastrointestinal haemorrhage, hypotension
and abdominal distension. Intestinal infections with organisms
such as Salmonella and Clostridium difficile should always be
considered in patients with diarrhoea.
When assessing gastrointestinal symptoms, the effect of
medication should always be considered before subjecting the
patient to often invasive investigations. Disease activity in other
systems is a clue that the gastrointestinal problem may be SLE
related. In patients with abdominal pain in whom infection has
been excluded and initial investigations are unhelpful, high-dose
immunosuppressive therapy should be given and a surgical
opinion sought early if there is no response.
diffuse segmentalIV-G(A/C) active and chronic lesions:
Renal featuresdiffuse global
IV-S(C) chronic lesions: diffuse
segmental
IV-G(C) chronic lesions: diffuse global
V Diffuse membranous
glomerulonephritis
V Membranous lupus nephritis
VI Advanced sclerosing
glomerulonephritis
VI Advanced sclerosis lupus nephritis
ISN, International Society of Nephrology; RPS, Renal Pathology Society;
WHO, World Health Organization.
About 30% of patients develop significant renal disease and lupus
nephritis is an important prognostic indicator for disease severity.
Symptoms can be minimal until substantial kidney damage has
occurred; therefore, regular monitoring is vital. Blood pressure
and urea and creatinine concentrations should also be measured
regularly. The WHO histological classification of lupus nephritis
(1988, revised 1995) has been revised by the International Society
of Nephrology (ISN)/Renal Pathology Society (RPS).6 The new
classification offers a more quantitative approach and allows for
incorporation of distinction between active and chronic inactive
lesions. This is summarized in Table 3.
Table 3
Assessment of glomerular diseaseAssessment of glomerular disease involves a urine dipstick test
for protein, red blood cells (RBCs) and white blood cells (WBCs);
if the dipstick is positive, urine microscopy should be performed,
looking for RBC and WBC casts (a marker of glomerular
inflammation). In the past, 24-h urine collections to assess
urinary protein loss or creatinine clearance were widely used, but
are gradually being superseded by the use of the proteinecrea-
tinine ratio on a ‘spot’ urine. In addition, more accurate
measurements of glomerular filtration rate can now be achieved
using the Cr-EDTA method, which is based on plasma radioac-
tivity at a set point in time after an intravenous dose.
Renal biopsy
Renal biopsy carries complications and should be performed in
patients in whom urinalysis is persistently abnormal or glomer-
ular filtration rate reduced. However, as clinical symptoms bear
little relationship to histological findings, a biopsy is often
required to stratify and to guide therapy. A quantitative
morphometric index of chronicity and damage may predict time
to renal failure and death.7
With adequate early treatment, few patients with renal
disease develop renal failure. Blood pressure control and
adequate immunosuppression are the keys to success, with
anticoagulation for patients with antiphospholipid syndrome.
Cutaneous manifestations
Figure 1 Cutaneous vasculitic rash in a patient with systemic lupus
erythematosus.
Cutaneous manifestations are present in up to 85% of SLE
patients and range from the classic malar butterfly rash and
maculopapular discoid lesions to vasculitic lesions on the fingers
MEDICINE 38:2 76
and toes (Figure 1). Many SLE rashes are photosensitive and this
can be an aid to diagnosis. Alopecia is common and seldom
scarring, but usually causes distress to the patient (Figure 2).
Subacute cutaneous lupus is a recognized variant associated with
anti-Ro antibodies and is usually benign. Lupus panniculitis is
a form of lipo-atrophy in which inflammation and necrosis of
subcutaneous fat are followed by scarring; it is uncommon and
can be disfiguring. Immunoglobulin (IgG or IgM) and comple-
ment are often deposited at the dermo-epidermal junction in both
lesional and non-lesional skin in lupus patients; this is the basis
of the lupus band test.
� 2009 Elsevier Ltd. All rights reserved.
Figure 2 Widespread non-scarring alopecia.
American College of Rheumatology 1999 nomenclatureof neuropsychiatric syndromes in systemic lupuserythematosus
Central nervous system
Aseptic meningitis
Cerebrovascular disease
Demyelinating syndrome
Headache (including migraine, benign intracranial hypertension)
Movement disorder (chorea)
Myelopathy
Seizure disorders
Acute confusional state
Anxiety disorder
Cognitive dysfunction
Mood disorder
Psychosis
Peripheral nervous system
Acute demyelinating polyradiculoneuropathy
(GuillaineBarre syndrome)
Autonomic disorder
Mononeuropathy, single/multiplex
Myasthenia gravis
Cranial neuropathy
Plexopathy
Polyneuropathy
Table 4
SLE
Neuropsychiatric manifestations
Neuropsychiatric SLE (NPSLE) is a major diagnostic and treatment
problem. It is estimated to affect 14e75% of patients and can be
associated with acute or chronic irreversible brain injury. The ACR
has recently revised its definition of NPSLE, distinguishing 12
central and seven peripheral types of neurological involvement
(Table 4). These are not recommended for diagnostic use. NPSLE
can manifest as CNS or peripheral nervous system disease, but it
must be remembered that these manifestations can have other
causes (e.g. hypertensive cerebrovascular disease).
Diagnosis of NPSLE remains clinical. Investigations are often
unhelpful in diagnosis, but are useful in excluding other causes
of cerebral dysfunction, such as malignancy and infection.
Lumbar puncture is useful to exclude infection and may show
raised protein concentrations, lymphocytes and/or oligoclonal
bands. EEG changes are often non-specific. Psychometric
testing can be helpful. Computed tomography (CT) scans are
insensitive to chronic white matter disease but can be used to
exclude haemorrhage or abscess. Magnetic resonance imaging
(MRI), preferably with contrast and diffusion-weighted
imaging, is the imaging modality of choice. MRI can reveal
white matter lesions that are often thought to represent small
infarcts, but does not readily distinguish small areas of cerebral
vasculitis from infarction. Single-photon emission CT scanning
is increasingly being used to identify functional (perfusion)
abnormalities in the brain.
MEDICINE 38:2 77
Haematological features
Normochromic, normocytic anaemia is present in up to 70% of
patients. Other causes of anaemia are renal impairment, NSAIDs,
Coombs’-positive haemolytic anaemia, dietary deficiency,
menstrual loss and permicious anaemia. Leucopenia and lym-
phopenia are common. Thrombocytopenia occurs in about 20%
of patients, either in a mild form associated with anti-
phospholipid antibody syndrome and risk of thrombosis or as
auto-immune thrombocytopenia with a risk of bleeding, which
responds to corticosteroids and/or splenectomy. The latter
manifestation may predate development of other signs of SLE.
Lymphadenopathy is common and usually non-tender.
Steadily enlarging tender lymph nodes suggest infection or
malignancy. Splenomegaly also occurs and hyposplenism can
develop late in the course of the disease.
Antiphospholipid antibodies and lupus anticoagulant are
found in about 30e40% of patients. Features of antiphospholipid
antibody syndrome include venous and arterial thrombosis,
recurrent foetal loss, livedo reticularis (Figure 3), headache and
epilepsy. Patients who have suffered a thrombotic episode
require lifelong anticoagulation. Studies of optimum treatment
are ongoing.
Serological features
Autoantibodies
At least 100 autoantigens have been found to be targets in SLE,
but few are clinically important. Antinuclear antibodies (ANA)
are positive in more than 95% of patients. Raised anti-dsDNA
� 2009 Elsevier Ltd. All rights reserved.
Figure 3 Livedo reticularis rash in a patient with antiphospholipid
syndrome.
SLE
antibody titres were found in 61% of patients in the authors’
London cohort of 401 SLE patients. Anti-dsDNA antibodies are
closely related to renal disease and an increase in titre should
alert the clinician to a possible flare of disease, particularly if it is
associated with decreasing C3 concentrations.
Of the antibodies to extractable nuclear antigens, anti-Ro
correlates well with photosensitive skin rashes and anti-Ro and
anti-La with Sjogren’s syndrome, congenital heart block and
neonatal lupus. Anti-Sm antibodies are highly SLE specific but
are present in only 10% of Caucasian and 30% of Afro-Caribbean
lupus patients. Anti-RNP antibodies are not specific for SLE and
can occur in patients with overflap syndromes (mixed connective
tissue disease). Because circulating immune complexes can
deposit in tissues and activate complement, a decrease in
complement factors C3/C4 and an increase in their degradation
products C3d/C4d can be seen in active disease.
Management
Treatment of SLE should be tailored to the manifestations of the
individual’s disease. All treatment plans should be discussed
fully with the patient and adverse effects of drug therapies
explained. Current therapies have significantly improved
survival (85% 10-year survival). With improved prognosis,
problems related to medication (e.g. diabetes mellitus, hyper-
cholesterolaemia) and problems related to chronic organ damage
MEDICINE 38:2 78
(hypertension and end-stage renal failure) must be addressed.
The aims of treatment are rapid and sustained control of disease
activity, minimization of adverse effects, reduced co-existent risk
factors and control of the long-term effects of disease and/or
drugs. Drug therapy in SLE is summarized in Table 5.
Measurement of disease activity and damage
Measurement of disease activity and damage is essential to the
clinician,8 as the basis of all treatment decisions. Several vali-
dated disease activity scores are now in use:
� Systemic Lupus Erythematosus Disease Activity Index
(SLEDAI)
� Systemic Lupus Activity Measure (SLAM)
� European Consensus Lupus Activity Measurement (ECLAM)
� British Isles Lupus Assessment Group (BILAG) index.
The first three are global score indices offering a relatively
crude guide to overall disease activity.8 The classic BILAG index
is based on the physician’s intention-to-treat principle and
provides an ‘at-a-glance’ view of activity in eight organs/
systems.8 A revised version, the BILAG-2004 index with nine
systems, has been validated and published. Around 10 major
trials of new therapies for SLE are in progress using the BILAG
system to assess lupus activity. As patient survival has increased,
a damage index has been developed that assesses permanent
scarring. The Systemic Lupus International Collaborating
Clinics/ACR damage index documents the number of items of
permanent organ damage since disease onset. The effect of SLE
on the patient’s health status is also important. The question-
naire SF36 is the most commonly used measure. In clinical
practice (time and personnel resources permitting), it is sug-
gested that one activity scale and laboratory assessment are
performed at each clinic visit, and the damage index and the
SF36 survey assessed annually.
General principles for management include:
� sun avoidance and use of high-factor sun-blocks on sun-
exposed areas
� lifestyle modification (exercise, smoking cessation, dietary
modification, stress management)
� infection risk reduction e e.g. vaccination (modified, live
viral immunizations should not be given to patients taking
>10 mg prednisolone daily or major immunosuppressive
drugs)
� calcium and vitamin D supplementation and/or bisphospho-
nate treatment when taking prednisolone
� cardiovascular risk factors should be assessed and corrected,
in particular the treatment of hypercholesterolaemia with
statins.
Mild disease
These patients have cutaneous or joint involvement only.
NSAIDs may be sufficient to control arthralgia and myalgia, and
sun-block should be used to prevent UV light-induced rashes. If
control is not achieved, hydroxychloroquine (an antimalarial
drug) can be used. The usual dose is 200e400 mg/day. Ocular
toxicity is recognized but rare. Some units undertake 12-monthly
ophthalmic follow-up, but in others, patients are provided with
Ishihara charts or are asked to see their optician annually and to
contact the unit if a change in vision is noticed. Hydroxy-
chloroquine has a mild lipid-lowering effect that may be useful in
� 2009 Elsevier Ltd. All rights reserved.
Drug therapy in systemic lupus erythematosus
Clinical feature NSAID Antimalarial Corticosteroids Cytotoxic agents
Fatigue � þ þ �Fever þ � þ �Serositis þ � þ �Arthralgia þ þ þ �Arthritis þ þ þ þMyalgia þ þ þ �Myositis � � þ þMalar rash � þ þ þAlopecia � þ þ �Raynaud’s phenomenon � � � �Pneumonitis � � þ þCarditis � � þ þVasculitis � � þ þNeuropsychiatric � � ? ?
Renal � � þ þHaemolytic anaemia � � þ þThrombocytopenia � � þ þ
þ, usually beneficial; �, not beneficial; ?, depends on manifestation.
NSAID, non-steroidal anti-inflammatory drug.
Modified from: Maddison PJ, Isenberg DA, Woo P, Glass DN, eds. Oxford textbook of rheumatology, 2nd edn. Oxford: Oxford University Press, 1998.
Table 5
SLE
cardiovascular disease prevention. In patients with isolated
cutaneous disease, treatment may be needed only during the
summer. Topical or intralesional corticosteroids can also be used
in those with cutaneous disease.
Moderate disease
These patients exhibit other organ involvement (not life-threat-
ening), often with constitutional symptoms. Such patients
require corticosteroids. A low dosage (<0.5 mg/kg) is often
sufficient. When control has been achieved, dosage should be
reduced gradually to the lowest possible. Rapid withdrawal can
lead to a rebound flare. Azathioprine is often useful in controlling
disease and reducing corticosteroid requirements. Regular blood
tests are needed to check for marrow suppression, particularly on
initiation of treatment. It is important to note the interaction with
allopurinol. Azathioprine is metabolized by xanthine oxidase, so
allopurinol should be avoided if possible. If it is used, the
azathioprine dose should be reduced by 75% and full blood
count monitored carefully.
Severe disease
These patients have major, life-threatening organ involvement,
such as cerebral disease, severe renal disease (proliferative lupus
nephritis) or major organ vasculitis. They require rapid, high-
dose immunosuppression. A Cochrane meta-analysis in 2003
showed that in proliferative lupus nephritis cyclophosphamide
with corticosteroids reduced the risk of renal function deterio-
ration compared to corticosteroids alone. The standard National
Institutes of Health regimen is 6-monthly pulses of 1 g/m2 fol-
lowed by quarterly pulses for 2 years: however, few patients are
MEDICINE 38:2 79
now treated this way. Lower or less frequent doses of cyclo-
phosphamide tend to be used, or replaced altogether by other
safer immunosuppressants, such as mycophenolate mofetil.
Corticosteroids are given orally or as an intravenous pulse.
However, there are concerns about the increased risk of infection
and possible malignancy, and there is a risk of infertility linked to
age (uncommon in the under-20s, invariable in the over-35s).
Therefore, once induction therapy has been successful, less toxic
drugs such as azathioprine can be used to maintain remission.
Mycophenolate mofetil (MMF) has been shown to be effica-
cious as induction therapy in prospective studies of proliferative
lupus nephritis, and can also be used as an alternative mainte-
nance agent to azathioprine. Although some trials have suggested
a lower infection rate and a similar relapse rate compared to
cyclophosphamide when used for induction, up to 10% of patients
develop a hypersensitivity reaction; it is also teratogenic and
should be stopped at least 3 months before a planned pregnancy.
Other therapies
� Methotrexate is used in the treatment of serositis and cuta-
neous and articular manifestations of lupus. It should be
avoided in pregnancy and necessitates regular blood moni-
toring of liver enzymes and bone marrow function.
� Oral dapsone therapy has been shown to be beneficial for
vasculitic lesions, subacute cutaneous SLE, oral ulcers and
thrombocytopenia. However, careful monitoring is needed
because of adverse effects, such as haemolysis and poly-
neuritis. Its use is currently limited to resistant cutaneous SLE.
� Dehydroepiandrosterone is a weak androgenic steroid that
may have a role in mild-to-moderate disease.
� 2009 Elsevier Ltd. All rights reserved.
SLE
With the success of anti-TNF therapy in rheumatoid arthritis,
there has been similar enthusiasm for the use of targeted bio-
logical immunosuppressant therapies in SLE. Many of the
following are now in, or have completed, Phase 3 clinical trials
and may be available for use in a non-trial context in the future.
� Rituximab, a chimeric (murine/human) monoclonal anti-
CD20 first developed as a treatment for B cell lymphoma, has
been shown to be efficacious in the treatment of rheumatoid
arthritis (RA). CD20 is expressed on the surface of all normal
B cells but not plasma cells. Data from its clinical use in
lymphoma as well as large clinical trials in RA have demon-
strated good tolerability. An open-label study in 50 SLE
patients in London has shown very promising efficacy.9
� Anti-Blys (B lymphocyte stimulator) likewise targets the
development and maturation of B cells and has been studied
in clinical trials but has yet to be approved for lupus.
� Abatacept, a combination of CTLA4-1g and the Fc portion of
IgG1, has been proposed as an important molecule blocking T
cell activation. Abatacept blocks the ‘second signal’ interac-
tion between antigen-presenting cells and T cells. It inhibits
the development of proteinuria in a murine model of SLE and
is now being investigated in human lupus. It is licensed for
use in patients with rheumatoid arthritis.
Pregnancy in SLE
Pregnancy and its outcome are major concerns in many patients.
Fertility is generally unaffected by disease. Pregnancy should be
considered when the woman’s health is optimal (ideally in clinical
remission for 6 months and with normal renal function). Appro-
priate counselling should be given to those who are anti-Ro/La
positive about the risk of neonatal lupus syndrome and congenital
heart block. During pregnancy the foetal heart rate should be
monitored weekly from week 16. Anticoagulation should be
considered for those with features of antiphospholipid syndrome.
The pregnancy requires close monitoring and should be managed
jointly by the obstetrician, with an interest in maternal and foetal
medicine, and either a rheumatologist or a nephrologist.
There is controversy about whether the risk of flare is
increased during pregnancy. Flares during pregnancy can occur
at any time and do not seem to be more serious than those
occurring in non-pregnant patients. However, the incidence of
pre-eclampsia is increased; risk factors include pre-existing
hypertension, lupus nephritis and the presence of anti-
phospholipid antibodies. The incidences of premature labour,
intrauterine death and growth retardation are increased as well.
It is recommended that NSAIDs are avoided in the last few
weeks of pregnancy because of the risk of premature closure of
MEDICINE 38:2 80
the ductus arteriosus. Corticosteroids and hydroxychloroquine
are not teratogenic. Azathioprine and ciclosporin should be
considered if more powerful immunosuppression is required, but
cyclophosphamide, methotrexate and mycophenolate are tera-
togenic and should be avoided for 3 months before a planned
pregnancy. A
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estrogen plus progestin in healthy postmenopausal women: principal
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JAMA 2002; 288: 321e33.
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prognosis in lupus nephritis. Q J Med 2003; 6: 411e20.
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Best Pract Res Clin Rheumatol 2005; 19: 685e708.
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FURTHER READING
Gordon C. Chapter 124: Assessing disease activity and outcome in SLE.
In: Hochberg MC, Silman AJ, Smolen JS, Weinblatt ME, Weisman MH,
eds. Rheumatology. 4th edn. Mosby, 2007: 1303e8.
Maddison PJ, Isenberg DA, Woo P, Glass DN, Breedveld F, eds. Oxford
textbook of rheumatology. 3rd edn. Oxford: Oxford University Press,
2004.
Morrow J, Nelson JL, Watts R, Isenberg D. Autoimmune rheumatic disease.
2nd edn. Oxford: Oxford University Press, 1999.
� 2009 Elsevier Ltd. All rights reserved.