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

Weight changes
Lupus may be associated with weight loss and weight gain.
Weight loss often occurs before the diagnosis of SLE is
ELS subject area: Immunology made. Unintentional weight loss may be due to decreased
appetite, the side eects of medications, gastrointestinal
How to cite: disease or the use of diuretics. See also: Hypothalamic
Schur, Peter H (March 2009) Systemic Lupus Erythematosus. In:
Control of Food Intake and Body Weight
Encyclopedia of Life Sciences (ELS). John Wiley & Sons, Ltd: Chichester.
DOI: 10.1002/9780470015902.a0002147.pub2
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 tomography, bronchoalveolar lavage and/or biopsy. Acute
inammation and scarring. See also: Glomerulonephritis pneumonitis can be fatal if untreated, but often becomes
Mesangial (type II) nephritis occurs in 1020% of cases. chronic, leading to pulmonary insuciency.
Immune deposits are detected primarily in the mesangium; Pulmonary hypertension is uncommon, and often un-
there are some minor urine (e.g. red cells, white cells, pro- recognized until detected too late. Patients may have some
tein) and serological (e.g. raised antideoxyribonucleic acid dyspnoea and chest pain, often detected by chance on
(DNA) antibodies and low complement levels) abnormal- echocardiography. When moderate to severe, the progno-
ities. Hypertension is uncommon; progression to renal sis is very poor. See also: Pulmonary Hypertension
failure is virtually never seen. Rare complications include the shrinking lung syndrome
Focal proliferative (type III) nephritis occurs in 1020% and pulmonary haemorrhage.
of patients. Histologically there are focal areas of
glomerular proliferation. There are signicant urinary Cardiovascular
and serological abnormalities, but hypertension and pro-
gression to renal insuciency are uncommon. Pericarditis is relatively common, although usually clini-
Diuse proliferative (type IV) nephritis is the most com- cally insignicant. Verrucous endocarditis (LibmanSacks
mon form. There are signicant urinary and serological disease) is usually clinically silent but can produce valvular
abnormalities, as well as hypertension and azotaemia. insuciency and serve as a source of emboli. Both are
There is considerable inammation and/or scarring of the usually detected by echocardiography. See also: Cardio-
glomeruli, as determined by pathological ndings. Un- vascular Disease: Epidemiology
treated, this usually progresses to renal failure. There is an increasing frequency of coronary artery dis-
Membranous (type V) nephritis also aects approxi- ease, as patients live longer, are treated with high-dose
mately 1020% of patients, who show peripheral oedema steroids, become hypertensive and are hyperlipaemic.
and signicant proteinuria, without other urine or sero-
logical abnormalities. Blood pressure is usually normal; Central nervous system
azotaemia is absent. Pathologically the basement mem-
Neurological and psychiatric complications occur in most
brane is thickened. The prognosis for survival is good with
patients. They may result directly from SLE, or from com-
appropriate therapy.
plications of the disease (e.g. hypertension, uraemia) and its
treatment. The most common neurological complications
Gastrointestinal tract are cognitive defects, usually characterized by memory
problems. In addition, patients may have generalized or
The gastrointestinal tract is often involved, manifesting with
partial complex seizures, strokes (usually due to thrombo-
abdominal pain. However, this is more commonly from the
sis) and peripheral neuropathy. Headaches are very com-
side eects of medication than from active SLE. Examples of
mon. As a result of brain involvement, or because of a
the former include gastritis and even peptic ulceration sec-
psychological reaction to this chronic potentially fatal dis-
ondary to the use of nonsteroidal anti-inammatory drugs
ease, patients often develop anxiety and/or depression.
(NSAIDs) and/or corticosteroids. However, SLE (mesen-
Complications include seizures due to uraemia, strokes
teric artery) vasculitis can lead to pancreatitis, peritonitis
from hypertension and meningitis (infectious or secondary
and colitis. Liver involvement from lupus is unusual and
to medications). The diagnosis is often assisted by electro-
presentation with liver function abnormalities and a positive
encephalography, MRI of the brain and/or examination of
antinuclear antibody (ANA) test result is more consistent
spinal uid. See also: Headache
with chronic active hepatitis (lupoid hepatitis).
Haematological
Pulmonary
Patients with SLE frequently develop abnormalities in each
Chest pain on breathing occurs in approximately 50% of of the three blood cell lines:
patients with SLE. This is usually due to chest wall muscle
pain, without inammation. The pain is aggravated by . Leucopenia is common. While diagnostically useful, it is
touch and/or movement. However, there may be inam- usually not symptomatic (predisposing to infection) un-
mation of the pleura (pleuritis), which causes pain on less severe.
breathing. Pleuritis is said to occur in approximately 50% . Many patients have mild anaemia, usually as a result of
of patients with lupus. It is often associated with a pleural the anaemia of chronic disease. Haemolytic anaemia is
eusion, which is usually small and mildly inammatory. rare, but can be very severe. See also: Anaemia: Overview
Approximately 10% of patients with SLE develop a . Thrombocytopenia is also frequently seen, although
pneumonitis characterized by fever, even haemoptysis, bleeding usually occurs only with platelet counts below
pleurisy, dyspnoea and pulmonary inltrates on chest ra- 25 000 mm3.
diography. Infection must be excluded. Pathologically,
there is a severe alveolitis with both neutrophils and mono- Other ndings include hypocomplementaemia and an
nuclear cells. Diagnosis may be facilitated by computed increase in the erythrocyte sedimentation rate, g-globulin

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Systemic Lupus Erythematosus

level and various ANA titres. Anticardiolipin antibodies, . serositis;


for example, can produce a false-positive test for syphilis; . nephritis or nephrotic syndrome;
however, some patients have a false-positive test for syph- . neurological symptoms such as seizures or psychosis;
ilis without anticardiolipin antibodies. . alopecia;
. phlebitis and
. recurrent abortion.
Precipitating Factors Lupus should also be suspected in young women pre-
senting with purpura, easy bruizing, diuse adenopathy,
The onset of SLE is infrequently attributed to a single
hepatosplenomegaly, peripheral neuropathy, endocarditis,
event, although most physicians have seen patients in
myocarditis, interstitial pneumonitis, or aseptic meningitis.
whom the disease began shortly after some event:
A positive Coombs test result, low complement levels and
. Exposure to the sun and other sources of UV light immune deposits at the dermalepidermal junction on skin
(especially UV-B, and to some extent UV-A) may biopsy are also suggestive of lupus.
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:
American Rheumatologic Association criteria
Energy, Radiation and Temperature Regulation in
Plants Most physicians rely on the ARA revised criteria for the
. Infections can initiate lupus or cause a relapse. classication of SLE (Table 2; Hochberg, 1997). It should be
. Stress has been implicated in causing exacerbations, noted that these criteria were developed for the classica-
particularly of mild disease. Unfortunately, stress as an tion of patients with SLE when SLE was compared with
entity has never been clinically dened, except as it re- other rheumatic diseases for study purposes. SLE is virtu-
lates to its psychosomatic eects. ally nonexistent among African blacks.
. Pregnancy can cause an exacerbation or even trigger the The diagnosis of SLE is made if four or more of the
rst symptoms of lupus; a relapse is more likely to de- manifestations are present, either serially or simultane-
velop in the postpartum period. Therapeutic abortion ously, during any interval of observations (Hochberg,
can also induce a relapse, perhaps via mechanisms re- 1997). When tested against other rheumatic diseases, these
lated to pregnancy or to the operation itself. See also: criteria have a sensitivity and specicity of approximately
Pregnancy: Maternal Disorders 96%.
A suggested classication of patients is as follows:
. classical SLE many criteria
. denite SLE four or more criteria
Clinical Criteria for Diagnosis . probable SLE three criteria
. possible SLE two criteria
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 Autoantibodies
abnormal serological test results helps to conrm the
diagnosis. The ANA test is the best screening test for SLE and should
It is important to recognize that patients may present be performed whenever SLE is suspected (Solomon et al.,
with only monosystem disease. Further, many of the com- 2002). The ANA test is positive in signicant titre (usually
mon manifestations are nonspecic. To make an accurate 1:160 or higher) in virtually all patients with SLE. Al-
diagnosis of SLE it is therefore always necessary to inter- though a positive ANA test has only 2035% predictive
pret the presenting complaint in terms of the past history. 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
Presenting symptoms of other disorders: Sjogren syndrome, 68%; scleroderma,
Lupus usually begins with one or several of the following 4075% (especially with a speckled pattern of ANA); ju-
symptoms: venile rheumatoid arthritis, 16% and rheumatoid arthritis,
2550% (especially with a diuse pattern of ANA).
. unexplained nonspecic symptoms such as fever, fa- Antibodies to double-stranded DNA (dsDNA) and to
tigue, weight loss or anaemia; the ribonucleic acid (RNA)protein complex Sm (Smith)
. photosensitive rash; are much more specic for SLE. Their sensitivity is ap-
. arthralgia or arthritis; proximately 75% and 25% respectively, and their speci-
. Raynaud phenomenon; city is over 90%.

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

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Systemic Lupus Erythematosus

Aetiology (vascular cell adhesion molecule (VCAM) and intercellu-


lar adhesion molecule (ICAM)). Oestrogen also causes in-
The aetiology of SLE remains unknown and is clearly creased macrophage protooncogene expression and
multifactorial. Many observations suggest a role for ge- enhanced adhesion of peripheral mononuclear cells to
netic, hormonal, immunological and environmental endothelium. In comparison, androgens tend to be
factors. immunosuppressive (Lahita, 1990). Serum levels of de-
hydroepiandrosterone (DHEA), an intermediate com-
Genetic factors pound in testosterone synthesis, are low in nearly all
patients with SLE. This may be mediated by impaired IL-2
The following observations are compatible with a genetic production in these patients. See also: Cytokines; Immu-
role in the pathogenesis of SLE (Schur, 1995): (a) there is a nological Adhesion and Homing Molecules
high concordance rate (1457%) of SLE in monozygotic Progesterone and prolactin also aect immune activity.
twins; and (b) 512% of relatives of patients with SLE have Progesterone downregulates T-cell proliferation and in-
the disease. creases the number of CD8 cells, whereas lupus ares have
A genetic predisposition for the development of SLE is been associated with hyperprolactinaemia.
also evidenced by the increased frequency of specic genetic
markers including: human leucocyte antigen HLA-DR2, Immune abnormalities
HLA-DR3, DQW1; deciency of complement components
C1q, C2 and C4; Gm, low levels of CR1; certain alleles of the There are numerous immune defects in patients with SLE.
Fc receptor; mannose-binding lectin polymorphisms; poly- However, the aetiology of these abnormalities remains un-
morphisms of cytokine and interferon (IFN) genes; toll-like clear; it is not known which defects are primary and which
receptors (TLRs); ITGAM (integrin alpha M)-ITGAX (in- are secondarily induced. In certain cases these immune de-
tegrin alpha X); interferon regulatory factor 5 (IRF5); B fects are episodic, and some correlate with disease activity.
lymphoid tyrosine kinase (BLK)/C8orf13 and PTPN22 SLE is primarily a disease with abnormalities in immune
(lymphoid protein tyrosine phosphatase 22) (Sestak et al., regulation (Hahn et al., 2005). These abnormalities are
2007). See also: Major Histocompatibility Complex: Human thought to be secondary to a loss of self-tolerance; thus,
Further support for genetic complexity in the pathogen- aected patients (either before or during disease evolution)
esis of SLE is provided by a year 2007 review of the genetics are no longer totally tolerant to all of their self-antigens,
of SLE that summarized results of studies of genome-wide and consequently develop an autoimmune response.
scanning in aected sibling pairs (Sestak et al., 2007). At See also: Autoimmune Disease: Pathogenesis; Immunolo-
least 9 loci on 6 dierent chromosomes have been reported gical Discrimination Between Self and Nonself
to be signicantly linked to SLE. They are: 1q23, 1q31-32, The following are some of the immune abnormalities
1q41-43, 2q37, 4p16, 6p11-21 (i.e. the MHC loci), 10q22- that have been described in SLE; how and whether they
23, 12q24 and 16q12-13. relate to the pathogenesis of SLE is not known:
It has been calculated that between four and eight genes
. a decrease in cytotoxic and suppressor T cells (which
are involved in predisposing individuals to SLE. Each gene
would normally downregulate immune responses).
presumably aects some aspect of immune regulation,
See also: T Lymphocytes: Cytotoxic
protein degradation, peptide transport across cell mem-
. impaired generation of polyclonal T-cell cytolytic
branes, complement, the reticuloendothelial system (in-
activity.
cluding phagocytosis), immunoglobulins, apoptosis or sex
. an increase in helper (CD4+) T cells. See also: T Lympho-
hormones. Dierent combinations of these independently
cytes: Helpers
segregating gene defects may cause distinct abnormal
. polyclonal activation of B cells and abnormal B-cell re-
responses, thereby resulting in separate pathological
ceptor signalling (Pugh-Bernard and Cambier, 2006).
processes and dierent clinical expressions. See also:
. defects in B-cell tolerance, perhaps related to defects in
Autoimmune Disease: Genetics
apoptosis, leading to prolonged life of B cells (Yurasov
et al., 2005).
Hormonal factors . dysfunctional signalling by SLE T cells.
. elevated circulating levels of IFNa and increased ex-
As mentioned earlier, increased oestrogenic activity may
pression of IFNa-inducible RNA transcripts by mono-
play a role in the epidemiology of SLE. This theory may
nuclear cells, especially in patients with active disease
explain at least in part the observation that SLE is much
(Feng et al., 2006; Ronnblom and Pascual, 2008).
more common among women, particularly in the child-
. abnormal TLR signalling, especially TLR 7 and 9
bearing years. The aetiological role of hormones in SLE
(Papadimitraki et al., 2006; Migita et al., 2007; Allam
may be related to their eects on immune responsiveness
and Anders, 2008).
(Grimaldi, 2006). Oestrogen stimulates thymocytes,
CD8+ and CD4+ T cells, B cells, macrophages, the re- These changes promote the production of ANAs
lease of certain cytokines (e.g. IL-1) and the expression of (see later discussion). In addition, patients may have a (ge-
both HLA and endothelial cell adhesion molecules netic) defect in apoptosis, resulting in abnormal

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programmed cell death (Graham and Utz, 2005). Apopto- UV light may stimulate keratinocytes to express more
tic cells are also poorly cleared in SLE, although anti- small nuclear ribonucleoproteins (snRNPs) on their cell
phospholipid antibodies enhance opsonization and surface, and to secrete more IL-1, IL-3, IL-6, gran-
clearance. The act of phagocytosis results in stimulation ulocytemacrophage colony-stimulating factor (GM-
of the immune response to autoantigens derived from the CSF) and tumour necrosis factor a (TNFa), thereby
apoptotic cells. See also: Apoptosis: Molecular Mechan- stimulating B cells to make more antibody. In addition
isms; Phagocytosis to the local eects in skin, UV light may also increase
These multiple defects cause a cascade of events that the degree of systemic autoimmunity by interfering with
begins with abnormal cellular breakdown and ends with antigen processing by and activation of macrophages.
the production of autoantibodies. As cells break down ab- UV light decreases T-cell DNA methylation, which may
normally, certain antigens (especially nuclear and cryptic lead to overexpression of lymphocyte function-associated
self-peptides) are processed, perhaps abnormally, into pep- antigen (LFA) 1. These T cells may then become auto-
tides by antigen-presenting cells (APCs) such as macro- reactive, resulting in autoantibody formation. See also:
phages, B lymphocytes and dendritic cells. Alternatively, Antigen Processing
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 Pathogenesis of Clinical
With either mechanism, a peptidemajor histocom-
patibility complex (MHC) forms and stimulates the ac- Manifestations
tivation and clonal expansion of CD4+ autoreactive T
cells. These cells, via release of cytokines (e.g. IL-4, IL-6 Although the exact aetiology of SLE remains obscure, it
and IL-10) (Kyttaris et al., 2005), cause autoreactive B is clear that many of the clinical manifestations of SLE
cells to become activated to proliferate and dierentiate are mediated directly or indirectly by antibody formation
into antibody-producing cells that make an excess of and the creation of immune complexes. As an example,
antibodies to many nuclear antigens. Thus, a specic immune complex deposition in the kidney is responsible
immune prole develops that is characterized by the de- for much of the tissue damage of lupus nephritis. These
velopment of raised levels of ANA, especially to DNA, complexes form either in the circulation, where they
Sm, RNP, Ro, La, nucleosomes and other nuclear an- are poorly cleared, or in situ, as free antibody binds to
tigens. See also: Major Histocompatibility Complex: free antigen that has already deposited in the glomerulus
Interaction with Peptides or is an intrinsic glomerular antigen. Once deposited,
ANAs are made to antigens from active sites on mole- immune complexes activate the complement system,
cules involved in essential cellular functions (such as RNA thereby generating chemotactic factors that attract leu-
splicing). With continued pressure over time from self- cocytes and mononuclear cells. These cells phagocytose
antigens, the immune response switches, via somatic immune complexes and release mediators (such as
(hyper)mutation, from low-anity highly cross-reactive cytokines and activators of the clotting system) that per-
immunoglobulin (Ig) M antibodies to high-anity IgG petuate the glomerular inammation. With continuing
antibodies, and then nally to antibodies directed towards immune complex deposition, chronic inammation may
more limited epitopes on self-antigens. Unique idiotypes of ensue, ultimately leading to brinoid necrosis, scarring
antibodies may then stimulate autoreactive T cells to ex- and reduced renal function. See also: AntigenAntibody
pand, thereby helping unique clones of B cells to expand. Complexes; Immune Complex Disease
The nal result is the production of more specic ANAs Immune complexes have also been detected (by
with unique idiotypes. See also: Antibody Responses: immunouorescence and/or electron microscopy) at the
Development; B Lymphocytes; Somatic Hypermutation in dermalepidermal junction in skin lesions, the choroid
Antibody Evolution 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
Environmental factors patients with SLE. See also: Fc Receptors
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 Treatment
antibodies to EpsteinBarr virus and make antibodies to
retroviruses, including protein regions homologous with Eective treatment requires ongoing patientdoctor com-
HLA antigens. Antibodies to these molecular mimicry munication to interpret laboratory tests correctly, alleviate
molecules may contribute to the development of autoim- symptoms, prevent and treat relapses, and lessen side
munity. See also: EpsteinBarr Virus; Molecular Mimicry eects related to drug therapy.

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Systemic Lupus Erythematosus

Determination of activity and severity Diet and nutrition


An eective therapeutic regimen rst requires the accurate A conservative approach is to recommend a balanced diet
determination of both disease activity and severity. Disease consisting of carbohydrates, proteins and fats. However,
activity usually refers to the degree of inammation, the diet should be modied based upon disease activity and
whereas severity implies that organ function and perhaps the response to therapy:
its underlying structure is quantitatively impaired. The de- . Patients with active inammatory disease and fever may
gree of organ dysfunction has been referred to as the dam- require an increase in caloric intake.
age index. . Corticosteroids enhance appetite, resulting in poten-
The presence of severe organ dysfunction does not nec- tially signicant weight gain. Hunger can be somewhat
essarily imply ongoing inammation. As an example, lessened by the ingestion of water, antacids, H2 blockers
marked proteinuria and decreased glomerular ltration and/or proton pump inhibitors. If, however, weight gain
rate may result from either active inammation or inactive is signicant, patients should receive instruction on low-
scarring. The ability to dierentiate between these two calorie diets.
possibilities is extremely important, as immunosuppressive . Signicant hyperlipidaemia may be induced by the
therapy is not indicated in the latter setting. 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-
Markers of activity tin) should be considered if cholesterol levels remain high
Disease activity is assessed using a combination of the despite a change in diet.
clinical history, physical examination, organ-specic func- . Vitamins are rarely needed when patients eat a ba-
tional tests and serological studies. As an example, active lanced diet. However, a daily multivitamin should
SLE (particularly lupus nephritis) is commonly associated be taken by patients who are not able to obtain an
with a rise in IgG anti-dsDNA titres, a fall in complement adequate diet or who are dieting to lose weight. In
levels (especially CH50, C3 and C4), and an increase in addition patients with lupus, as they are advised to
complement split products (Sturfelt and Truedsson, 2005). avoid the sun and/or use sun screen regularly, should take
Increases in the erythrocyte sedimentation rate and in supplemental vitamin D (Kamen and Aranow, 2008).
C-reactive protein (CRP) levels are also commonly seen in . Patients on long-term steroids and postmenopausal
active disease. CRP concentration is particularly raised in women should also ingest 400800 units vitamin D plus
patients with infection. However, not all patients with these 1000 mg calcium per day to minimize the degree of bone
serological markers have active disease and these markers loss. If there is osteopenia/osteoporosis as demonstrated
do not necessarily predict disease exacerbation. See also: by bone density therapy with a bisphosphonate should
Acute-phase Proteins; Autoimmune Disease: Diagnosis be recommended.
Other, more investigatory laboratory tests also may re- . Herbs are of unproven benet, and may cause harm.
ect disease activity, including:

. soluble T-cell activation markers raised serum levels of Exercise


CD25, CD27, CD30 and CD50 (ICAM-3); Inactivity produced by acute illness causes a rapid loss of
. cytokines raised serum levels of IL-2 receptor, IL-6, muscle mass and stamina. Fatigue may therefore ensue
IFNg and IL-10; once the illness subsides. This can usually be treated
. adhesion molecules increased serum levels of VCAM- with graded exercise. In selected refractory cases, relief
1, P-selectin and endothelial leucocyte adhesion mole- of fatigue can be obtained with prednisone, and/or
cule (ELAM) 1; dierent studies have found either raised antimalarials.
or normal levels of ICAM-1, whereas E-selectin levels
are generally unchanged; Immunizations
. cell surface expression of very late activation antigen
It had previously been thought that immunization could
(VLA) 4 and LFA-1 in lupus vasculitis; LFA-1, E-
exacerbate SLE. However, inuenza vaccine has now been
selectin, VCAM-1 and ICAM-1 in SL and
shown to be safe and eective in patients with SLE;
. increase serum and cell expression of IFNa (Ronnblom
pneumococcal vaccine is also safe but resultant antibody
and Pascual, 2008).
titres are lower in patients with SLE than in controls. In
contrast, it is inadvisable to immunize potentially immuno-
suppressed patients with live vaccines.
General treatment considerations
Although organ involvement requires specic drug ther- Avoidance of specific medications
apy, a number of general issues are applicable to every Anecdotal data suggest that sulfonamide antibiotics and
patient with SLE. penicillin (but not the synthetic penicillins) may cause

8 ENCYCLOPEDIA OF LIFE SCIENCES & 2009, John Wiley & Sons, Ltd. www.els.net
Systemic Lupus Erythematosus

exacerbations and should therefore be avoided. In contrast, medications that deplete B lymphocytes (e.g. rituximab,
medications that cause drug-induced lupus, such as pro- epratuzumab) and one that activates the B-cell factors
cainamide and hydralazine, do not cause exacerbations of APRIL (B cell proliferation inducing ligand) and B cell
idiopathic SLE. This observation is a presumed reection of activating factor (BAFF)/B lymphocyte stimulator (BLyS)
the pathogenetic dierences between the two disorders. (atacicept) (Tieng and Peeva, 2008). Furthermore, many
more agents that aect tolerance, B cells, chemokines,
cytokines, inammation and innate immunity (including
Pregnancy and contraception
TLRs) are being studied in animal (e.g. mouse) models of
Pregnancy should be avoided during active disease (espe- SLE (Davidson and Aranow, 2006). By contrast, anti-TNF
cially with signicant organ impairment) due to the high risk biologics, which are so eective in the treatment of rheu-
of miscarriage. Women with SLE should be counselled not matoid arthritis, have been avoided in the treatment of
to become pregnant until the disease has been quiescent for SLE, because they frequently cause a drug-induced lupus
at least 6 months. See also: Pregnancy: Maternal Disorders syndrome.
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-
Prognosis
graine headaches, Raynaud syndrome, a history of phle-
SLE can run a varied clinical course, ranging from a relatively
bitis or antiphospholipid antibodies probably should not
benign illness to a rapidly progressive disease with fulminant
take oral estrogen-containing contraceptives.
organ failure and death. Most patients have a relapsing and
Pregnant patients with active lupus are generally man-
remitting course, which is usually managed with the use of
aged with corticosteroids. Other drugs used during
high-dose steroids during the treatment of severe ares.
pregnancy include NSAIDs and hydroxychloroquine
(probably safe). Cyclophosphamide, mycophenolate and
Patient survival
methotrexate are contraindicated; however, azathioprine
can be used cautiously. The survival rate of patients with SLE has increased dra-
matically over the past several decades, from approximately
Treatment of specific organ involvement 40% at 5 years in the 1950s to approximately 90% at 15 years
at the present time. The likelihood of survival can be ranked
A number of medications are commonly used in the treat- on the basis of organ involvement (skin and musculoskeletal
ment of SLE, including NSAIDs, antimalarials (primarily are highest; CNS and renal are lowest) and on the number of
hydroxychloroquine), corticosteroids (primarily prednis- American College of Rheumatology criteria for SLE present
one) and immunosuppressive agents (primarily cyclo- (the higher the number, the worse the prognosis).
phosphamide, mycophenolate and azathioprine). What The improvement in patient survival is probably a result
follows is a general overview of which drugs are preferred in of multiple factors. These include increased disease recog-
selected clinical settings. nition with more sensitive diagnostic tests, earlier diagnosis
NSAIDs are generally eective for musculoskeletal or treatment, the inclusion of milder cases, and increasingly
complaints and mild serositis. Antimalarials are most use- judicious therapy and prompt treatment of complications.
ful for skin manifestations and for musculoskeletal com- The major cause of death in the rst few years of illness is
plaints that do not adequately respond to NSAIDs. active disease (e.g. CNS, renal or cardiovascular disease),
See also: History of Antimalarial Agents whereas late deaths are caused either by the illness or by
Systemic corticosteroids used alone or in combination treatment complications (including infection and coronary
with immunosuppressive agents are reserved for patients disease).
with signicant organ involvement, particularly renal, Serious infection is most often due to immunosuppres-
CNS disease and haematological manifestations. See also: sive therapy. Patients at particular risk are those treated
Immunosuppressive Drugs with both corticosteroids and immunosuppressives, espe-
Treatment with prednisone as soon as a signicant rise in cially if the white blood cell count is less than 3000 mL21
anti-dsDNA occurred prevented relapses in most cases in a and/or high-dose steroids are given.
study of 156 patients (Bootsma et al., 1995). The present Premature coronary artery disease is being increasingly
author follows such patients closely but does not treat titres recognized as a cause of late mortality; this has been at-
in the absence of clinical evidence of active disease. See also: tributed primarily to accelerated atherosclerosis associated
Autoimmune Disease: Treatment with corticosteroid use (Karp et al., 2008). See also:
Cardiovascular Disease: Epidemiology
The relation of SLE to cancer is unclear because con-
New Biologic Therapies icting data have been reported. Multiple studies have
found either no change, an increase, or a decrease in the
A number of newer immunosuppressive agents are being cancer rate, a decrease in cancer rate but an increase in non-
investigated in formal therapeutic trials. These include Hodgkin lymphoma (Bernatsky et al., 2006). The largest

ENCYCLOPEDIA OF LIFE SCIENCES & 2009, John Wiley & Sons, Ltd. www.els.net 9
Systemic Lupus Erythematosus

study of 1585 Danish patients with SLE found a 5-fold 10-year period. A comparison of early and late manifestations
increase in the risk of non-Hodgkin lymphoma, as well as in a cohort of 1,000 patients. Medicine (Baltimore) 82: 299.
an increase in lung, liver and vaginalvulval cancer. Davidson A and Aranow C (2006) Pathogenesis and treatment of
See also: Non-Hodgkin Lymphomas systemic lupus erythematosus nephritis. Current Opinion in
Rheumatology 18: 468475.
Poor prognosis for survival in SLE includes: Drenkard C, Villa AR, Garcia-Padilla C et al. (1996) Remission of
systemic lupus erythematosus. Medicine 75: 8898.
. renal disease (especially diuse proliferative glomerulo- Feng X, Wu H, Grossman JM et al. (2006) Association of in-
nephritis); creased interferon-inducible gene expression with disease ac-
. hypertension; tivity and lupus nephritis in patients with systemic lupus
. male sex; erythematosus. Arthritis and Rheumatism 54: 2951.
. young age; Graham KL and Utz PJ (2005) Sources of autoantigens in sys-
. older age at presentation; temic lupus erythematosus. Current Opinion in Rheumatology
. black race, which may primarily reect low socio- 17: 513.
economic status; Grimaldi CM (2006) Sex and systemic lupus erythematosus: the
. poor socioeconomic status; role of the sex hormones estrogen and prolactin on the regu-
. presence of antiphospholipid antibodies and lation of autoreactive B cells. Current Opinion in Rheumatology
. high overall disease activity. 18: 456461.
Hahn BH, Ebling F, Singh RR et al. (2005) Cellular and molecular
mechanisms of regulation of autoantibody production in lupus.
Annals of the New York Academy of Sciences 1051: 433.
Morbidity Heller CA and Schur PH (1985) Serological and clinical remission
in SLE. Journal of Rheumatology 12: 916918.
Despite the reduction in long-term mortality, patients with Hochberg MC (1997) Updating the American College of Rheu-
SLE are still at risk for signicant morbidity due to both matology Revised criteria for the classication of systemic lupus
active disease and the side eects of drugs such as cortico- erythematosus. Arthritis and Rheumatism 40: 1725.
steroids and immunosuppressive agents. Steroid-induced Kamen DA and Aranow CB (2008) Vitamin D in Systemic Lupus
avascular necrosis of the hips and knees has become a par- Erythematosus. Current Opinion in Rheumatology 20: 532537.
ticularly important problem as patients live longer with the Karp I, Abrahamowicz M, Fortin PR et al. (2008) Recent cor-
illness. ticosteroid use and recent disease activity: independent deter-
minants of coronary heart disease risk factors in systemic lupus
erythematosus? Arthritis and Rheumatism 59: 169.
Remission
King JK and Hahn BH (2007) Systemic lupus erythematosus:
Although a major focus has been on improving mortality modern straegies for management a moving target. Best
and morbidity rates in SLE, it is becoming increasingly Practice & Research Clinical Rheumatology 21: 971987.
recognized that many patients have a clinical remission Kyttaris VC, Juang YT and Tsokos GC (2005) Immune cells and
requiring no treatment. In a recent study of 667 patients, cytokines in systemic lupus erythematosus: an update. Current
approximately 25% had treatment-free remission lasting Opinion in Rheumatology 17: 518.
for at least 1 year (Drenkard et al., 1996). Remission oc- Lahita RG (1990) Sex hormones and the immune system. Part 1.
Human data. Baillie`res Clinical Rheumatology 4: 112.
curred in 50% of those with disease of more than 18 years
Lockshin MD (2006) Sex dierences in autoimmune disease.
duration, and in 75% of those with disease of over 30 years
Lupus 15: 753.
duration. Remission was also seen in some patients who
Migita K, Miyashita T, Maeda Y et al. (2007) Toll-like receptor
had severe renal disease. In another report, 6% of 300 pa- expression in lupus peripheral blood mononuclear cells. Journal
tients went into long-lasting clinical and serological remis- of Rheumatology 34: 493.
sion (i.e. a negative ANA test result) (Heller and Schur, Papadimitraki ED, Choulaki C, Koutala E et al. (2006) Expan-
1985). sion of toll-like receptor 9-expressing B cells in active systemic
lupus erythematosus: implications for the induction and main-
tenance of the autoimmune process. Arthritis and Rheumatism
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10 ENCYCLOPEDIA OF LIFE SCIENCES & 2009, John Wiley & Sons, Ltd. www.els.net
Systemic Lupus Erythematosus

Solomon DH, Kavanaugh AJ and Schur PH (2002) Evidence- Further Reading


based guidelines for the use of immunologic tests: antinuclear
antibody testing. Arthritis and Rheumatism 47: 434444. Aladjem H and Schur PH (1986) In Search of the Sun. New York:
Sturfelt G and Truedsson L (2005) Complement and its break- Scribners.
down products in SLE. Rheumatology 44: 12271232. Lahita R (2004) Systemic Lupus Erythematosus, 4th edn. New
Tieng AT and Peeva E (2008) B-cell-directed therapies in systemic York: Churchill Livingstone.
lupus erythematosus. Seminars in Arthritis & Rheumatism 38: Schur PH (ed.) (1996) The Clinical Management of Systemic Lupus
218227. Erythematosus, 2nd edn. Philadelphia: Lippincott.
Yurasov S, Wardemann H, Hammersen J et al. (2005) Defective B Schur PH (2008) Multiple chapters on Systemic Lupus Erythe-
cell tolerance checkpoints in systemic lupus erythematosus. matosus in Up To Date in Rheumatology.
Journal of Experimental Medicine 201: 703. Wallace DJ and Hahn BH (2006) Dubois Lupus Erythematosus,
Zandman-Goddard G and Shoenfeld Y (2005) Infectons and 7th edn. Lippincott.
SLE. Autoimmunity 38: 473485.

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