Systemic Lupus Advanced article

Erythematosus . Introduction
Article Contents

Peter H Schur, Brigham and Womens Hospital, Boston, Massachusetts, USA . Constitutional Symptoms

. Fatigue

. Specific Organ Symptoms

Systemic lupus erythematosus is a chronic inflammatory disease of unknown cause
. Precipitating Factors
which can affect the skin, joints, kidneys, lungs, nervous system, serous membranes and
. Clinical Criteria for Diagnosis
other organs in the body, in various combinations, especially in young women, and
. Epidemiology
which is characterized by immune abnormalities, in particular antibodies to nuclear
. Aetiology
constituents. Treatment is based both on preventive measures, alleviation of symptoms,
. Pathogenesis of Clinical Manifestations
but in particular anti-inflammatory agents including nonsteroidal anti-inflammatory
. Treatment
drugs, corticosteroids and immunosuppressive medications.
. New Biologic Therapies

. Prognosis

Online posting date: 15th March 2009

Introduction Constitutional Symptoms

Systemic lupus erythematosus (SLE) is a chronic
inammatory disease of unknown cause, which can
aect the skin, joints, kidneys, lungs, nervous system, se-
rous membranes and other organs of the body. Distinct
immunological abnormalities, especially the production
of a number of antinuclear antibodies, are another
prominent feature of the disease. The clinical course of
SLE is characterized by periods of remissions and
chronic or acute relapses. Women, especially in their 20s
and 30s, are aected more frequently than men. Treatment
is based on preventive measures, reversal of inammation,
prevention of organ impairment and alleviation of symp-
toms (King and Hahn, 2007) See also: Inammation:
Chronic
Patients with SLE are subject to a myriad of symptoms,
complaints and inammatory involvement that can aect
virtually every organ (Cervera et al., 2003). The most com-
mon pattern is a mixture of constitutional complaints with
skin, musculoskeletal, mild haematological and serological
involvement (Table 1). However, some patients have pre-
dominantly haematological, renal or central nervous sys-
tem (CNS) manifestations. The pattern that dominates
during the rst few years of illness tends to prevail
subsequently.
Fatigue, fever and weight loss are typically present at
some point during the course of the disease, occurring in
50100% of patients.
Fatigue
Fatigue is the most common complaint, and occasionally
the most debilitating. It occurs in 80100% of patients,
even when no other feature of active disease is present.
Fatigue is strongly associated with diminished exercise
tolerance.
It is important to distinguish the fatigue due to lupus
from that caused by other factors. The association of the
onset of fatigue with other features or laboratory tests
suggesting active lupus makes it probable that the fatigue is
due to lupus.
However, fatigue is usually not due to active SLE but to
one or more of the following: increased workload, depres-
sion, unhealthy habits (smoking, fad diets, sedentary liv-
ing, drug abuse), stress, anaemia, hypothyroidism, use of
certain medications (including prednisone, b-blockers),
any inammatory and/or infectious disease, coexistent -
bromyalgia, sleep disturbances and/or deconditioning.

ELS subject area: Immunology
How to cite:
Schur, Peter H (March 2009) Systemic Lupus Erythematosus. In:
Encyclopedia of Life Sciences (ELS). John Wiley & Sons, Ltd: Chichester.
DOI: 10.1002/9780470015902.a0002147.pub2
Weight changes
Lupus may be associated with weight loss and weight gain.
Weight loss often occurs before the diagnosis of SLE is
made. Unintentional weight loss may be due to decreased
appetite, the side eects of medications, gastrointestinal
disease or the use of diuretics. See also: Hypothalamic
Control of Food Intake and Body Weight
Weight gain in SLE is usually due to one of the two
factors: salt and water retention associated with the

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 Systemic Lupus Erythematosus

Table 1 Frequency of symptoms of systemic lupus Specific Organ Symptoms

erythematosusa
SLE aects multiple organ systems. The course is marked
Present at by remissions and relapses, and may vary from mild to
Present at onset anytime severe.
Symptom (%) (%)
Fatigue 50 74100 Musculoskeletal manifestations
Fever 36 4080+
Weight loss 21 4460+ Musculoskeletal symptoms occur in virtually all patients
Arthritis or arthralgia 6267 8395 and are often the earliest manifestation. Most common are
Skin 73 8091 arthralgia and myalgia. Arthritis tends to be migratory
Buttery rash 2838 4850+ and asymmetrical. Usually, only a few joints are aected,
Photosensitivity 29  60 especially the hands and knees. The arthritis is moderately
Mucuous 1021 2752 painful, and rarely deforming. Synovial eusions are in-
membrane lesion frequent, usually small, and only mildly inammatory.
Alopecia 32 5571 Radiographs usually show no abnormality. See also:
Raynaud 1733 3071 Musculoskeletal System Overview
phenomenon Unfortunately many patients, particularly those on
Purpura 10 1534 chronic high-dose steroids, are susceptible to avascular
Urticaria 1 48 necrosis, especially of the hip. These are best detected early
Renal 1638 5073 by magnetic resonance imaging (MRI). See also: Magnetic
Nephrosis 5 1118 Resonance Imaging
Gastrointestinal 18 3844 Osteoporosis is also a common problem, especially in
Pulmonary 212 2498 patients receiving corticosteroids.
Pleurisy 17 3045
Eusion 24 Skin
Pneumonia 29 Most patients have skin lesions at some time during the
Cardiac 15 2046 course of the illness. The most common lesion is the but-
Pericarditis 8 848 tery rash, erythema over the cheeks and nose, which
Murmurs 23 appears after sun (i.e. ultraviolet (UV) light) exposure. It
ECG changes 3470 lasts only a few days, but often recurs. Some patients de-
Lymphadenopathy 716 3150 velop discoid lesions, typically in sun-exposed areas. These
Splenomegaly 5 920 are characterized by discrete, slightly inltrated plaques
Hepatomegaly 2 725 covered by a well-formed adherent scale that extends into
Central nervous system 1221 2575 dilated (e.g. plugged) hair follicles. They tend to expand
Functional Most slowly with inammation at the periphery, and then heal,
Psychosis 1 552 leaving depressed central scars, telangiectasia, and areas of
Convulsions 0.5 220 increased or decreased skin pigment. Another photosensi-
a
Adapted from Von Feldt JM (1995) Systemic lupus erythemato- tive skin lesion is subacute cutaneous lupus. Lesions start as
sus. Recognizing its various presentations. Postgraduate Medicine scaly erythematous papules but develop into either
97: 79. psoriasiform or annular large lesions. Hair loss is com-
mon, but baldness is not. Many patients develop oral
ulcers, which are usually painless, in contrast to herpetic
nephrotic syndrome, or increased appetite associated with chancre sores. Raynaud phenomenon is a frequent prob-
the use of corticosteroids. lem and may antedate other features of the disease. Patients
typically have periungal erythema. Vasculitis is uncommon
but, when present, resembles leucoclastic vasculitis.
Fever
Kidney
Fever is seen in over 50% of patients with SLE (Cervera
et al., 2003). The pattern of fever may be helpful diagnos- Renal involvement becomes clinically apparent in approx-
tically. Episodic fever is suggestive of active SLE or infec- imately 50% of patients; however, most of the remaining
tion; in comparison, sustained fever may reect CNS patients have subclinical disease that can be demonstrated
involvement or an adverse reaction to a drug. on electron microscopy of renal biopsies. Renal involve-
Infectious complications, especially of the respiratory ment usually develops in the rst few years of illness, and
and urinary systems, develop in approximately 50% of should be detected early by periodic urinalysis, quantita-
patients with SLE. Opportunistic infections are a common tion of proteinuria and estimation of the glomerular ltra-
cause of death (Zandman-Goddard and Shoenfeld, 2005). tion rate. Several forms of glomerulonephritis can occur,

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and renal biopsy is useful to dene the type and degree of
inammation and scarring. See also: Glomerulonephritis
Mesangial (type II) nephritis occurs in 1020% of cases.
Immune deposits are detected primarily in the mesangium;
there are some minor urine (e.g. red cells, white cells, pro-
tein) and serological (e.g. raised antideoxyribonucleic acid
(DNA) antibodies and low complement levels) abnormal-
ities. Hypertension is uncommon; progression to renal
failure is virtually never seen.
Focal proliferative (type III) nephritis occurs in 1020%
of patients. Histologically there are focal areas of
glomerular proliferation. There are signicant urinary
and serological abnormalities, but hypertension and pro-
gression to renal insuciency are uncommon.
Diuse proliferative (type IV) nephritis is the most com-
mon form. There are signicant urinary and serological
abnormalities, as well as hypertension and azotaemia.
There is considerable inammation and/or scarring of the
glomeruli, as determined by pathological ndings. Un-
treated, this usually progresses to renal failure.
Membranous (type V) nephritis also aects approxi-
mately 1020% of patients, who show peripheral oedema
and signicant proteinuria, without other urine or sero-
logical abnormalities. Blood pressure is usually normal;
azotaemia is absent. Pathologically the basement mem-
brane is thickened. The prognosis for survival is good with
appropriate therapy.
Gastrointestinal tract
The gastrointestinal tract is often involved, manifesting with
abdominal pain. However, this is more commonly from the
side eects of medication than from active SLE. Examples of
the former include gastritis and even peptic ulceration sec-
ondary to the use of nonsteroidal anti-inammatory drugs
(NSAIDs) and/or corticosteroids. However, SLE (mesen-
teric artery) vasculitis can lead to pancreatitis, peritonitis
and colitis. Liver involvement from lupus is unusual and
presentation with liver function abnormalities and a positive
antinuclear antibody (ANA) test result is more consistent
with chronic active hepatitis (lupoid hepatitis).
Pulmonary
Chest pain on breathing occurs in approximately 50% of
patients with SLE. This is usually due to chest wall muscle
pain, without inammation. The pain is aggravated by
touch and/or movement. However, there may be inam-
mation of the pleura (pleuritis), which causes pain on
breathing. Pleuritis is said to occur in approximately 50%
of patients with lupus. It is often associated with a pleural
eusion, which is usually small and mildly inammatory.
Approximately 10% of patients with SLE develop a
pneumonitis characterized by fever, even haemoptysis,
pleurisy, dyspnoea and pulmonary inltrates on chest ra-
diography. Infection must be excluded. Pathologically,
there is a severe alveolitis with both neutrophils and mono-
nuclear cells. Diagnosis may be facilitated by computed
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Systemic Lupus Erythematosus
tomography, bronchoalveolar lavage and/or biopsy. Acute
pneumonitis can be fatal if untreated, but often becomes
chronic, leading to pulmonary insuciency.
Pulmonary hypertension is uncommon, and often un-
recognized until detected too late. Patients may have some
dyspnoea and chest pain, often detected by chance on
echocardiography. When moderate to severe, the progno-
sis is very poor. See also: Pulmonary Hypertension
Rare complications include the shrinking lung syndrome
and pulmonary haemorrhage.
Cardiovascular
Pericarditis is relatively common, although usually clini-
cally insignicant. Verrucous endocarditis (LibmanSacks
disease) is usually clinically silent but can produce valvular
insuciency and serve as a source of emboli. Both are
usually detected by echocardiography. See also: Cardio-
vascular Disease: Epidemiology
There is an increasing frequency of coronary artery dis-
ease, as patients live longer, are treated with high-dose
steroids, become hypertensive and are hyperlipaemic.
Central nervous system
Neurological and psychiatric complications occur in most
patients. They may result directly from SLE, or from com-
plications of the disease (e.g. hypertension, uraemia) and its
treatment. The most common neurological complications
are cognitive defects, usually characterized by memory
problems. In addition, patients may have generalized or
partial complex seizures, strokes (usually due to thrombo-
sis) and peripheral neuropathy. Headaches are very com-
mon. As a result of brain involvement, or because of a
psychological reaction to this chronic potentially fatal dis-
ease, patients often develop anxiety and/or depression.
Complications include seizures due to uraemia, strokes
from hypertension and meningitis (infectious or secondary
to medications). The diagnosis is often assisted by electro-
encephalography, MRI of the brain and/or examination of
spinal uid. See also: Headache
Haematological
Patients with SLE frequently develop abnormalities in each
of the three blood cell lines:
. Leucopenia is common. While diagnostically useful, it is
usually not symptomatic (predisposing to infection) un-
less severe.
. Many patients have mild anaemia, usually as a result of
the anaemia of chronic disease. Haemolytic anaemia is
rare, but can be very severe. See also: Anaemia: Overview
. Thrombocytopenia is also frequently seen, although
bleeding usually occurs only with platelet counts below
25 000 mm3.
Other ndings include hypocomplementaemia and an
increase in the erythrocyte sedimentation rate, g-globulin
3
 Systemic Lupus Erythematosus
level and various ANA titres. Anticardiolipin antibodies,
for example, can produce a false-positive test for syphilis;
however, some patients have a false-positive test for syph-
ilis without anticardiolipin antibodies.
Precipitating Factors
The onset of SLE is infrequently attributed to a single
event, although most physicians have seen patients in
whom the disease began shortly after some event:
. Exposure to the sun and other sources of UV light
(especially UV-B, and to some extent UV-A) may
cause exacerbations or even induce the rst sign
of lupus. The relapse is usually limited to a rash, al-
though other symptoms may develop. See also:
Energy, Radiation and Temperature Regulation in
Plants
. Infections can initiate lupus or cause a relapse.
. Stress has been implicated in causing exacerbations,
particularly of mild disease. Unfortunately, stress as an
entity has never been clinically dened, except as it re-
lates to its psychosomatic eects.
. Pregnancy can cause an exacerbation or even trigger the
rst symptoms of lupus; a relapse is more likely to de-
velop in the postpartum period. Therapeutic abortion
can also induce a relapse, perhaps via mechanisms re-
lated to pregnancy or to the operation itself. See also:
Pregnancy: Maternal Disorders
Clinical Criteria for Diagnosis
The diagnosis of SLE is usually made in a patient who
presents with one or more of the following symptom com-
plexes which satisfy the American Rheumatologic Associ-
ation (ARA) criteria. The presence of one or more
abnormal serological test results helps to conrm the
diagnosis.
It is important to recognize that patients may present
with only monosystem disease. Further, many of the com-
mon manifestations are nonspecic. To make an accurate
diagnosis of SLE it is therefore always necessary to inter-
pret the presenting complaint in terms of the past history.
Presenting symptoms
Lupus usually begins with one or several of the following
symptoms:
. unexplained nonspecic symptoms such as fever, fa-
tigue, weight loss or anaemia;
. photosensitive rash;
. arthralgia or arthritis;
. Raynaud phenomenon;
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. serositis;
. nephritis or nephrotic syndrome;
. neurological symptoms such as seizures or psychosis;
. alopecia;
. phlebitis and
. recurrent abortion.
Lupus should also be suspected in young women pre-
senting with purpura, easy bruizing, diuse adenopathy,
hepatosplenomegaly, peripheral neuropathy, endocarditis,
myocarditis, interstitial pneumonitis, or aseptic meningitis.
A positive Coombs test result, low complement levels and
immune deposits at the dermalepidermal junction on skin
biopsy are also suggestive of lupus.
American Rheumatologic Association criteria
Most physicians rely on the ARA revised criteria for the
classication of SLE (Table 2; Hochberg, 1997). It should be
noted that these criteria were developed for the classica-
tion of patients with SLE when SLE was compared with
other rheumatic diseases for study purposes. SLE is virtu-
ally nonexistent among African blacks.
The diagnosis of SLE is made if four or more of the
manifestations are present, either serially or simultane-
ously, during any interval of observations (Hochberg,
1997). When tested against other rheumatic diseases, these
criteria have a sensitivity and specicity of approximately
96%.
A suggested classication of patients is as follows:
. classical SLE many criteria
. denite SLE four or more criteria
. probable SLE three criteria
. possible SLE two criteria
Autoantibodies
The ANA test is the best screening test for SLE and should
be performed whenever SLE is suspected (Solomon et al.,
2002). The ANA test is positive in signicant titre (usually
1:160 or higher) in virtually all patients with SLE. Al-
though a positive ANA test has only 2035% predictive
value, the specicity is almost 100%; the probability of
having SLE is less than 0.14% if the ANA test is negative.
See also: Autoimmune Disease
ANAs are also present, usually in lower titre, in a variety
of other disorders: Sjogren syndrome, 68%; scleroderma,
4075% (especially with a speckled pattern of ANA); ju-
venile rheumatoid arthritis, 16% and rheumatoid arthritis,
2550% (especially with a diuse pattern of ANA).
Antibodies to double-stranded DNA (dsDNA) and to
the ribonucleic acid (RNA)protein complex Sm (Smith)
are much more specic for SLE. Their sensitivity is ap-
proximately 75% and 25% respectively, and their speci-
city is over 90%.
 Systemic Lupus Erythematosus

Table 2 American Rheumatologic Association criteria for diagnosis of systemic lupus erythematosus
Criterion Denition
Malar rash Fixed erythema, at or raised, over the malar eminences; tending to spare the nasolabial
folds
Discoid rash Erythematous raised patches with adherent keratotic scaling and follicular plugging;
atrophic scarring may occur in older lesions
Photosensitivity Skin rash as a result of unusual reaction to sunlight; causation established by patient history
or physician observation
Oral ulcers Oral or nasopharyngeal ulceration, usually painless, observed by a physician
Arthritis Nonerosive arthritis involving two or more peripheral joints, characterized by tenderness,
swelling or eusion
Serositis Pleuritis with convincing history of pleuritic pain or rub heard by a physician, or evidence of
pleural eusion; or pericarditis documented by electrocardiogram, rub or evidence of
pericardial eusion
Renal disorder Persistent proteinuria greater than 0.5 g day21, or greater than 3 g day21 if quantitation not
performed; or cellular casts which may be red cell, haemoglobin, granular, tubular or mixed
Neurological disorder Seizures or psychosis in the absence of oending drugs or known metabolic derangements
(uraemia, ketoacidosis or electrolyte imbalance)
Haematological disorder Haemolytic anaemia with reticulocytosis; or leucopenia with less than 4000 cells per mm3
total on two or more occasions; or lymphopenia with less than 1500 cells per mm3 on two or
more occasions; or thrombocytopenia with less than 100 000 platelets per mm3 in the absence
of oending drugs
Immunological disorder Positive for antiphospholipid antibody; or presence of anti-DNA antibody (antibody to
native DNA) present in abnormal titre; or presence of anti-Sm antibody (antibody to Sm
nuclear antigen); or false positive serological test for syphilis, known to be positive for at
least 6 months and conrmed by Treponema pallidum immobilization or uorescent
treponemal antibody absorption test
Antinuclear antibody An abnormal titre of antinuclear antibody by immunouorescence, or an equivalent assay,
at any point in time and in the absence of drugs known to be associated with drug-induced
lupus syndrome

Other autoantibodies are associated with specic clinical
manifestations:
. antibodies to single-stranded DNA and nucleosomes,
found frequently in SLE, rheumatoid arthritis and other
rheumatic diseases
. antibodies to ribonucleoprotein (RNP) in SLE, MCTD,
RA, Raynauds and scleroderma
. antibodies to Ro (SS-A) and La (SS-B) in SLE and
Sjogren syndrome
. anti-dsDNA with lupus nephritis
. anti-Ro with photosensitivity, neonatal lupus, C2 de-
ciency and subacute cutaneous lupus
. anti-ribosomal P protein with lupus psychosis, cerebritis
and/or depression.
Antiphospholipid antibodies
Patients with SLE may form antibodies to phospholipids
including a phospholipidb2-glycoprotein I complex.
b2-glycoprotein I normally has an anticoagulant eect that
is diminished by this antibody formation. This may explain
why antiphospholipid antibodies are implicated in the aeti-
ology of arterial and venous thrombosis (causing strokes
and thrombophlebitis) and in placental infarcts (causing
miscarriage). Antiphospholipid antibodies are detected by
three tests: Lupus anticoagulant, anticardiolipin and anti-
bodies to b2-glycoprotein I.
Epidemiology
The reported prevalence of SLE in the population is 40150
cases per 100 000. There is an increased frequency of SLE
among women that has been thought to be due to an oes-
trogen hormonal eect (see the section on Hormonal fac-
tors). This oestrogenic eect has been thought to explain
the female-to-male ratio of SLE in dierent age groups: in
children, in whom sex hormonal eects are presumably
minimal, the female-to-male ratio is approximately 3:1; in
adults the ratio ranges from 10 to 15:1; in older individuals
the ratio is approximately 8:1. Sixty-ve per cent of patients
with SLE have disease onset between the ages of 16 and 55
years. However, other possibilities for female predisposi-
tion have been suggested including X-inactivation, X- or
Y-chromosome genetic modulation and other factors
(Lockshin, 2006). See also: Sex Hormones in Vertebrates

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 Systemic Lupus Erythematosus
Aetiology
The aetiology of SLE remains unknown and is clearly
multifactorial. Many observations suggest a role for ge-
netic, hormonal, immunological and environmental
factors.
Genetic factors
The following observations are compatible with a genetic
role in the pathogenesis of SLE (Schur, 1995): (a) there is a
high concordance rate (1457%) of SLE in monozygotic
twins; and (b) 512% of relatives of patients with SLE have
the disease.
A genetic predisposition for the development of SLE is
also evidenced by the increased frequency of specic genetic
markers including: human leucocyte antigen HLA-DR2,
HLA-DR3, DQW1; deciency of complement components
C1q, C2 and C4; Gm, low levels of CR1; certain alleles of the
Fc receptor; mannose-binding lectin polymorphisms; poly-
morphisms of cytokine and interferon (IFN) genes; toll-like
receptors (TLRs); ITGAM (integrin alpha M)-ITGAX (in-
tegrin alpha X); interferon regulatory factor 5 (IRF5); B
lymphoid tyrosine kinase (BLK)/C8orf13 and PTPN22
(lymphoid protein tyrosine phosphatase 22) (Sestak et al.,
2007). See also: Major Histocompatibility Complex: Human
Further support for genetic complexity in the pathogen-
esis of SLE is provided by a year 2007 review of the genetics
of SLE that summarized results of studies of genome-wide
scanning in aected sibling pairs (Sestak et al., 2007). At
least 9 loci on 6 dierent chromosomes have been reported
to be signicantly linked to SLE. They are: 1q23, 1q31-32,
1q41-43, 2q37, 4p16, 6p11-21 (i.e. the MHC loci), 10q22-
23, 12q24 and 16q12-13.
It has been calculated that between four and eight genes
are involved in predisposing individuals to SLE. Each gene
presumably aects some aspect of immune regulation,
protein degradation, peptide transport across cell mem-
branes, complement, the reticuloendothelial system (in-
cluding phagocytosis), immunoglobulins, apoptosis or sex
hormones. Dierent combinations of these independently
segregating gene defects may cause distinct abnormal
responses, thereby resulting in separate pathological
processes and dierent clinical expressions. See also:
Autoimmune Disease: Genetics
Hormonal factors
As mentioned earlier, increased oestrogenic activity may
play a role in the epidemiology of SLE. This theory may
explain at least in part the observation that SLE is much
more common among women, particularly in the child-
bearing years. The aetiological role of hormones in SLE
may be related to their eects on immune responsiveness
(Grimaldi, 2006). Oestrogen stimulates thymocytes,
CD8+ and CD4+ T cells, B cells, macrophages, the re-
lease of certain cytokines (e.g. IL-1) and the expression of
both HLA and endothelial cell adhesion molecules
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(vascular cell adhesion molecule (VCAM) and intercellu-
lar adhesion molecule (ICAM)). Oestrogen also causes in-
creased macrophage protooncogene expression and
enhanced adhesion of peripheral mononuclear cells to
endothelium. In comparison, androgens tend to be
immunosuppressive (Lahita, 1990). Serum levels of de-
hydroepiandrosterone (DHEA), an intermediate com-
pound in testosterone synthesis, are low in nearly all
patients with SLE. This may be mediated by impaired IL-2
production in these patients. See also: Cytokines; Immu-
nological Adhesion and Homing Molecules
Progesterone and prolactin also aect immune activity.
Progesterone downregulates T-cell proliferation and in-
creases the number of CD8 cells, whereas lupus ares have
been associated with hyperprolactinaemia.
Immune abnormalities
There are numerous immune defects in patients with SLE.
However, the aetiology of these abnormalities remains un-
clear; it is not known which defects are primary and which
are secondarily induced. In certain cases these immune de-
fects are episodic, and some correlate with disease activity.
SLE is primarily a disease with abnormalities in immune
regulation (Hahn et al., 2005). These abnormalities are
thought to be secondary to a loss of self-tolerance; thus,
aected patients (either before or during disease evolution)
are no longer totally tolerant to all of their self-antigens,
and consequently develop an autoimmune response.
See also: Autoimmune Disease: Pathogenesis; Immunolo-
gical Discrimination Between Self and Nonself
The following are some of the immune abnormalities
that have been described in SLE; how and whether they
relate to the pathogenesis of SLE is not known:
. a decrease in cytotoxic and suppressor T cells (which
would normally downregulate immune responses).
See also: T Lymphocytes: Cytotoxic
. impaired generation of polyclonal T-cell cytolytic
activity.
. an increase in helper (CD4+) T cells. See also: T Lympho-
cytes: Helpers
. polyclonal activation of B cells and abnormal B-cell re-
ceptor signalling (Pugh-Bernard and Cambier, 2006).
. defects in B-cell tolerance, perhaps related to defects in
apoptosis, leading to prolonged life of B cells (Yurasov
et al., 2005).
. dysfunctional signalling by SLE T cells.
. elevated circulating levels of IFNa and increased ex-
pression of IFNa-inducible RNA transcripts by mono-
nuclear cells, especially in patients with active disease
(Feng et al., 2006; Ronnblom and Pascual, 2008).
. abnormal TLR signalling, especially TLR 7 and 9
(Papadimitraki et al., 2006; Migita et al., 2007; Allam
and Anders, 2008).
These changes promote the production of ANAs
(see later discussion). In addition, patients may have a (ge-
netic) defect in apoptosis, resulting in abnormal

programmed cell death (Graham and Utz, 2005). Apopto-
tic cells are also poorly cleared in SLE, although anti-
phospholipid antibodies enhance opsonization and
clearance. The act of phagocytosis results in stimulation
of the immune response to autoantigens derived from the
apoptotic cells. See also: Apoptosis: Molecular Mechan-
isms; Phagocytosis
These multiple defects cause a cascade of events that
begins with abnormal cellular breakdown and ends with
the production of autoantibodies. As cells break down ab-
normally, certain antigens (especially nuclear and cryptic
self-peptides) are processed, perhaps abnormally, into pep-
tides by antigen-presenting cells (APCs) such as macro-
phages, B lymphocytes and dendritic cells. Alternatively,
microorganisms may be broken down within APCs into
mimicry peptides that have sucient structural similarity
with immunodominant self-peptides. See also: Antigen-
presenting Cells; Molecular Mimicry
With either mechanism, a peptidemajor histocom-
patibility complex (MHC) forms and stimulates the ac-
tivation and clonal expansion of CD4+ autoreactive T
cells. These cells, via release of cytokines (e.g. IL-4, IL-6
and IL-10) (Kyttaris et al., 2005), cause autoreactive B
cells to become activated to proliferate and dierentiate
into antibody-producing cells that make an excess of
antibodies to many nuclear antigens. Thus, a specic
immune prole develops that is characterized by the de-
velopment of raised levels of ANA, especially to DNA,
Sm, RNP, Ro, La, nucleosomes and other nuclear an-
tigens. See also: Major Histocompatibility Complex:
Interaction with Peptides
ANAs are made to antigens from active sites on mole-
cules involved in essential cellular functions (such as RNA
splicing). With continued pressure over time from self-
antigens, the immune response switches, via somatic
(hyper)mutation, from low-anity highly cross-reactive
immunoglobulin (Ig) M antibodies to high-anity IgG
antibodies, and then nally to antibodies directed towards
more limited epitopes on self-antigens. Unique idiotypes of
antibodies may then stimulate autoreactive T cells to ex-
pand, thereby helping unique clones of B cells to expand.
The nal result is the production of more specic ANAs
with unique idiotypes. See also: Antibody Responses:
Development; B Lymphocytes; Somatic Hypermutation in
Antibody Evolution
Environmental factors
The environment may have a role in the aetiology of SLE
via its eects on the immune system.
Viruses, for example, may stimulate specic cells in this
immune network. Patients with SLE have higher titres of
antibodies to EpsteinBarr virus and make antibodies to
retroviruses, including protein regions homologous with
HLA antigens. Antibodies to these molecular mimicry
molecules may contribute to the development of autoim-
munity. See also: EpsteinBarr Virus; Molecular Mimicry
ENCYCLOPEDIA OF LIFE SCIENCES & 2009, John Wiley & Sons, Ltd. www.els.net
Systemic Lupus Erythematosus
UV light may stimulate keratinocytes to express more
small nuclear ribonucleoproteins (snRNPs) on their cell
surface, and to secrete more IL-1, IL-3, IL-6, gran-
ulocytemacrophage colony-stimulating factor (GM-
CSF) and tumour necrosis factor a (TNFa), thereby
stimulating B cells to make more antibody. In addition
to the local eects in skin, UV light may also increase
the degree of systemic autoimmunity by interfering with
antigen processing by and activation of macrophages.
UV light decreases T-cell DNA methylation, which may
lead to overexpression of lymphocyte function-associated
antigen (LFA) 1. These T cells may then become auto-
reactive, resulting in autoantibody formation. See also:
Antigen Processing
Pathogenesis of Clinical
Manifestations
Although the exact aetiology of SLE remains obscure, it
is clear that many of the clinical manifestations of SLE
are mediated directly or indirectly by antibody formation
and the creation of immune complexes. As an example,
immune complex deposition in the kidney is responsible
for much of the tissue damage of lupus nephritis. These
complexes form either in the circulation, where they
are poorly cleared, or in situ, as free antibody binds to
free antigen that has already deposited in the glomerulus
or is an intrinsic glomerular antigen. Once deposited,
immune complexes activate the complement system,
thereby generating chemotactic factors that attract leu-
cocytes and mononuclear cells. These cells phagocytose
immune complexes and release mediators (such as
cytokines and activators of the clotting system) that per-
petuate the glomerular inammation. With continuing
immune complex deposition, chronic inammation may
ensue, ultimately leading to brinoid necrosis, scarring
and reduced renal function. See also: AntigenAntibody
Complexes; Immune Complex Disease
Immune complexes have also been detected (by
immunouorescence and/or electron microscopy) at the
dermalepidermal junction in skin lesions, the choroid
plexus, the pericardium and the pleural cavity.
The rate at which immune complexes are cleared by Fc
receptors on monocytesmacrophages in the liver and
spleen from the circulation may be genetically impaired in
patients with SLE. See also: Fc Receptors
Treatment
Eective treatment requires ongoing patientdoctor com-
munication to interpret laboratory tests correctly, alleviate
symptoms, prevent and treat relapses, and lessen side
eects related to drug therapy.
7
 Systemic Lupus Erythematosus
Determination of activity and severity
An eective therapeutic regimen rst requires the accurate
determination of both disease activity and severity. Disease
activity usually refers to the degree of inammation,
whereas severity implies that organ function and perhaps
its underlying structure is quantitatively impaired. The de-
gree of organ dysfunction has been referred to as the dam-
age index.
The presence of severe organ dysfunction does not nec-
essarily imply ongoing inammation. As an example,
marked proteinuria and decreased glomerular ltration
rate may result from either active inammation or inactive
scarring. The ability to dierentiate between these two
possibilities is extremely important, as immunosuppressive
therapy is not indicated in the latter setting.
Markers of activity
Disease activity is assessed using a combination of the
clinical history, physical examination, organ-specic func-
tional tests and serological studies. As an example, active
SLE (particularly lupus nephritis) is commonly associated
with a rise in IgG anti-dsDNA titres, a fall in complement
levels (especially CH50, C3 and C4), and an increase in
complement split products (Sturfelt and Truedsson, 2005).
Increases in the erythrocyte sedimentation rate and in
C-reactive protein (CRP) levels are also commonly seen in
active disease. CRP concentration is particularly raised in
patients with infection. However, not all patients with these
serological markers have active disease and these markers
do not necessarily predict disease exacerbation. See also:
Acute-phase Proteins; Autoimmune Disease: Diagnosis
Other, more investigatory laboratory tests also may re-
ect disease activity, including:
. soluble T-cell activation markers raised serum levels of
CD25, CD27, CD30 and CD50 (ICAM-3);
. cytokines raised serum levels of IL-2 receptor, IL-6,
IFNg and IL-10;
. adhesion molecules increased serum levels of VCAM-
1, P-selectin and endothelial leucocyte adhesion mole-
cule (ELAM) 1; dierent studies have found either raised
or normal levels of ICAM-1, whereas E-selectin levels
are generally unchanged;
. cell surface expression of very late activation antigen
(VLA) 4 and LFA-1 in lupus vasculitis; LFA-1, E-
selectin, VCAM-1 and ICAM-1 in SL and
. increase serum and cell expression of IFNa (Ronnblom
and Pascual, 2008).
General treatment considerations
Although organ involvement requires specic drug ther-
apy, a number of general issues are applicable to every
patient with SLE.
8 ENCYCLOPEDIA OF LIFE SCIENCES & 2009, John Wiley & Sons, Ltd. www.els.net
Diet and nutrition
A conservative approach is to recommend a balanced diet
consisting of carbohydrates, proteins and fats. However,
the diet should be modied based upon disease activity and
the response to therapy:
. Patients with active inammatory disease and fever may
require an increase in caloric intake.
. Corticosteroids enhance appetite, resulting in poten-
tially signicant weight gain. Hunger can be somewhat
lessened by the ingestion of water, antacids, H2 blockers
and/or proton pump inhibitors. If, however, weight gain
is signicant, patients should receive instruction on low-
calorie diets.
. Signicant hyperlipidaemia may be induced by the
nephrotic syndrome or the administration of cortico-
steroids.
. Patients with hyperlipidaemia should be encouraged to
eat a low-fat diet. A lipid-lowering agent (usually a sta-
tin) should be considered if cholesterol levels remain high
despite a change in diet.
. Vitamins are rarely needed when patients eat a ba-
lanced diet. However, a daily multivitamin should
be taken by patients who are not able to obtain an
adequate diet or who are dieting to lose weight. In
addition patients with lupus, as they are advised to
avoid the sun and/or use sun screen regularly, should take
supplemental vitamin D (Kamen and Aranow, 2008).
. Patients on long-term steroids and postmenopausal
women should also ingest 400800 units vitamin D plus
1000 mg calcium per day to minimize the degree of bone
loss. If there is osteopenia/osteoporosis as demonstrated
by bone density therapy with a bisphosphonate should
be recommended.
. Herbs are of unproven benet, and may cause harm.
Exercise
Inactivity produced by acute illness causes a rapid loss of
muscle mass and stamina. Fatigue may therefore ensue
once the illness subsides. This can usually be treated
with graded exercise. In selected refractory cases, relief
of fatigue can be obtained with prednisone, and/or
antimalarials.
Immunizations
It had previously been thought that immunization could
exacerbate SLE. However, inuenza vaccine has now been
shown to be safe and eective in patients with SLE;
pneumococcal vaccine is also safe but resultant antibody
titres are lower in patients with SLE than in controls. In
contrast, it is inadvisable to immunize potentially immuno-
suppressed patients with live vaccines.
Avoidance of specific medications
Anecdotal data suggest that sulfonamide antibiotics and
penicillin (but not the synthetic penicillins) may cause

exacerbations and should therefore be avoided. In contrast,
medications that cause drug-induced lupus, such as pro-
cainamide and hydralazine, do not cause exacerbations of
idiopathic SLE. This observation is a presumed reection of
the pathogenetic dierences between the two disorders.
Pregnancy and contraception
Pregnancy should be avoided during active disease (espe-
cially with signicant organ impairment) due to the high risk
of miscarriage. Women with SLE should be counselled not
to become pregnant until the disease has been quiescent for
at least 6 months. See also: Pregnancy: Maternal Disorders
Oral contraceptives containing high-dose oestrogens can
cause exacerbations of SLE. However, this complication
rarely occurs with the current use of low-dose oestrogen- or
progesterone-containing compounds. Patients with mi-
graine headaches, Raynaud syndrome, a history of phle-
bitis or antiphospholipid antibodies probably should not
take oral estrogen-containing contraceptives.
Pregnant patients with active lupus are generally man-
aged with corticosteroids. Other drugs used during
pregnancy include NSAIDs and hydroxychloroquine
(probably safe). Cyclophosphamide, mycophenolate and
methotrexate are contraindicated; however, azathioprine
can be used cautiously.
Treatment of specific organ involvement
A number of medications are commonly used in the treat-
ment of SLE, including NSAIDs, antimalarials (primarily
hydroxychloroquine), corticosteroids (primarily prednis-
one) and immunosuppressive agents (primarily cyclo-
phosphamide, mycophenolate and azathioprine). What
follows is a general overview of which drugs are preferred in
selected clinical settings.
NSAIDs are generally eective for musculoskeletal
complaints and mild serositis. Antimalarials are most use-
ful for skin manifestations and for musculoskeletal com-
plaints that do not adequately respond to NSAIDs.
See also: History of Antimalarial Agents
Systemic corticosteroids used alone or in combination
with immunosuppressive agents are reserved for patients
with signicant organ involvement, particularly renal,
CNS disease and haematological manifestations. See also:
Immunosuppressive Drugs
Treatment with prednisone as soon as a signicant rise in
anti-dsDNA occurred prevented relapses in most cases in a
study of 156 patients (Bootsma et al., 1995). The present
author follows such patients closely but does not treat titres
in the absence of clinical evidence of active disease. See also:
Autoimmune Disease: Treatment
New Biologic Therapies
A number of newer immunosuppressive agents are being
investigated in formal therapeutic trials. These include
ENCYCLOPEDIA OF LIFE SCIENCES & 2009, John Wiley & Sons, Ltd. www.els.net
Systemic Lupus Erythematosus
medications that deplete B lymphocytes (e.g. rituximab,
epratuzumab) and one that activates the B-cell factors
APRIL (B cell proliferation inducing ligand) and B cell
activating factor (BAFF)/B lymphocyte stimulator (BLyS)
(atacicept) (Tieng and Peeva, 2008). Furthermore, many
more agents that aect tolerance, B cells, chemokines,
cytokines, inammation and innate immunity (including
TLRs) are being studied in animal (e.g. mouse) models of
SLE (Davidson and Aranow, 2006). By contrast, anti-TNF
biologics, which are so eective in the treatment of rheu-
matoid arthritis, have been avoided in the treatment of
SLE, because they frequently cause a drug-induced lupus
syndrome.
Prognosis
SLE can run a varied clinical course, ranging from a relatively
benign illness to a rapidly progressive disease with fulminant
organ failure and death. Most patients have a relapsing and
remitting course, which is usually managed with the use of
high-dose steroids during the treatment of severe ares.
Patient survival
The survival rate of patients with SLE has increased dra-
matically over the past several decades, from approximately
40% at 5 years in the 1950s to approximately 90% at 15 years
at the present time. The likelihood of survival can be ranked
on the basis of organ involvement (skin and musculoskeletal
are highest; CNS and renal are lowest) and on the number of
American College of Rheumatology criteria for SLE present
(the higher the number, the worse the prognosis).
The improvement in patient survival is probably a result
of multiple factors. These include increased disease recog-
nition with more sensitive diagnostic tests, earlier diagnosis
or treatment, the inclusion of milder cases, and increasingly
judicious therapy and prompt treatment of complications.
The major cause of death in the rst few years of illness is
active disease (e.g. CNS, renal or cardiovascular disease),
whereas late deaths are caused either by the illness or by
treatment complications (including infection and coronary
disease).
Serious infection is most often due to immunosuppres-
sive therapy. Patients at particular risk are those treated
with both corticosteroids and immunosuppressives, espe-
cially if the white blood cell count is less than 3000 mL21
and/or high-dose steroids are given.
Premature coronary artery disease is being increasingly
recognized as a cause of late mortality; this has been at-
tributed primarily to accelerated atherosclerosis associated
with corticosteroid use (Karp et al., 2008). See also:
Cardiovascular Disease: Epidemiology
The relation of SLE to cancer is unclear because con-
icting data have been reported. Multiple studies have
found either no change, an increase, or a decrease in the
cancer rate, a decrease in cancer rate but an increase in non-
Hodgkin lymphoma (Bernatsky et al., 2006). The largest
9
 Systemic Lupus Erythematosus
study of 1585 Danish patients with SLE found a 5-fold
increase in the risk of non-Hodgkin lymphoma, as well as
an increase in lung, liver and vaginalvulval cancer.
See also: Non-Hodgkin Lymphomas
Poor prognosis for survival in SLE includes:
. renal disease (especially diuse proliferative glomerulo-
nephritis);
. hypertension;
. male sex;
. young age;
. older age at presentation;
. black race, which may primarily reect low socio-
economic status;
. poor socioeconomic status;
. presence of antiphospholipid antibodies and
. high overall disease activity.
Morbidity
Despite the reduction in long-term mortality, patients with
SLE are still at risk for signicant morbidity due to both
active disease and the side eects of drugs such as cortico-
steroids and immunosuppressive agents. Steroid-induced
avascular necrosis of the hips and knees has become a par-
ticularly important problem as patients live longer with the
illness.
Remission
Although a major focus has been on improving mortality
and morbidity rates in SLE, it is becoming increasingly
recognized that many patients have a clinical remission
requiring no treatment. In a recent study of 667 patients,
approximately 25% had treatment-free remission lasting
for at least 1 year (Drenkard et al., 1996). Remission oc-
curred in 50% of those with disease of more than 18 years
duration, and in 75% of those with disease of over 30 years
duration. Remission was also seen in some patients who
had severe renal disease. In another report, 6% of 300 pa-
tients went into long-lasting clinical and serological remis-
sion (i.e. a negative ANA test result) (Heller and Schur,
1985).
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ENCYCLOPEDIA OF LIFE SCIENCES & 2009, John Wiley & Sons, Ltd. www.els.net
Systemic Lupus Erythematosus
Further Reading
Aladjem H and Schur PH (1986) In Search of the Sun. New York:
Scribners.
Lahita R (2004) Systemic Lupus Erythematosus, 4th edn. New
York: Churchill Livingstone.
Schur PH (ed.) (1996) The Clinical Management of Systemic Lupus
Erythematosus, 2nd edn. Philadelphia: Lippincott.
Schur PH (2008) Multiple chapters on Systemic Lupus Erythe-
matosus in Up To Date in Rheumatology.
Wallace DJ and Hahn BH (2006) Dubois Lupus Erythematosus,
7th edn. Lippincott.
11