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


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


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 segmental
IV-G(A/C) active and chronic lesions:
Renal features
diffuse 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 disease
Assessment 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.


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


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


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.


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

REFERENCES

1 Sanchez-Guerrero J, Karlson EW, Liang MH, Hunter DJ, Speizer FE,

Colditz GA. Past use of oral contraceptives and the risk of developing

systemic lupus erythematosus. Arthritis Rheum 1997; 40: 804e8.

2 Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of

estrogen plus progestin in healthy postmenopausal women: principal

results from the Women’s Health Initiative randomized controlled trial.

JAMA 2002; 288: 321e33.

3 Salmon M, Gordon C. The role of apoptosis in systemic lupus eryth-

ematosis. Rheumatology 1999; 38: 1177e83.

4 Karrar A, Sequeira W, Block JA. Coronary artery disease in systemic

lupus erythematosus: a critical review of the epidemiological

evidence. Semin Arthritis Rheum 2001; 30: 436e43.

5 Sultan SM, Ioannou Y, Isenberg DA. A review of gastrointestinal

manifestations of systemic lupus erythematosus. Rheumatology 1999;

38: 917e32.

6 Weening JJ, D’Agati VD, Schwartz MM, et al. The classification of

glomerulonephritis in systemic lupus erythematosus revisited. J Am

Soc Nephrol 2004; 15: 241e50.

7 Howie AJ, Turhan H, Adu D. Powerful morphometric indicator of

prognosis in lupus nephritis. Q J Med 2003; 6: 411e20.

8 Griffiths B, Mosca M, Gordon C. Assessment of patients with systemic

lupus erythematosus and the use of lupus disease activity indices.

Best Pract Res Clin Rheumatol 2005; 19: 685e708.

9 Lu TY, Ng KP, Cambridge G, et al. A retrospective seven-year analysis of

the use of B cell depletion therapy in systemic lupus erythematosus at

University College London hospital: the first fifty patients. Arthritis

Rheum 2009; 61: 482e7.

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.


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