SYSTEMIC LUPUS

ERYTHEMATOSUS
(SLE)

Systemic lupus erythematosus (SLE) is an

autoimmune disease in which organs and cells
undergo damage initially mediated by tissuebinding autoantibodies and immune
complexes.
In most patients, autoantibodies are present for a
few years before the first clinical symptom
appears; clinical manifestations are
heterogeneous. Ninety percent of patients at
diagnosis are women of childbearing years;
people of all genders, ages, and ethnic groups are
susceptible. Prevalence of SLE in the United
States is 10 to 400 per 100,000 depending on
race and gender; highest prevalence is in black
women and lowest is in white men.

PATHOGENESIS AND ETIOLOGY

Interactions between susceptibility genes and environmental
factors result in abnormal immune responses, which vary
among different patients.
Those responses may include
(1) activation of innate immunity (dendritic cells,
monocyte/macrophages) by CpG DNA, DNA in immune
complexes, viral RNA, and RNA in RNA/protein self-antigens; (2)
lowered activation thresholds and abnormal activation pathways
in adaptive immunity cells (T and B lymphocytes); (3) ineffective
regulatory CD4+ and CD8+ T cells; and
(4) reduced clearance of immune complexes and of apoptotic cells.
Self-antigens (nucleosomal DNA/protein; RNA/protein in Sm, Ro,
and La; phospholipids) are available for recognition by the
immune system in surface blebs of apoptotic cells; thus antigens,
autoantibodies, and immune complexes persist for
prolonged periods of time, allowing inflammation and
disease to develop.

Immune cell activation is accompanied by increased secretion of

proinflammatory type 1 and 2 interferons (IFNs), tumor necrosis
factor (TNF-), interleukin (IL)-17 and B cellmaturation/survival
cytokines B lymphocyte stimulator (BLyS/BAFF), and IL-10.
Upregulation of genes induced by interferons is a genetic "signature" in
peripheral blood cells of SLE in approximately 50% of patients.
Decreased production of other cytokines also contributes to SLE: Lupus
T and natural killer (NK) cells fail to produce enough IL-2 and
transforming growth factor (TGF-) to induce and sustain regulatory
CD4+ and CD8+ T cells.
The result of these abnormalities is sustained production of
autoantibodies and immune complexes; pathogenic subsets bind target
tissues, with activation of complement, leading to release of cytokines,
chemokines, vasoactive peptides, oxidants, and destructive enzymes.
This is accompanied by influx into target tissues of T cells,
monocyte/macrophages, and dendritic cells, as well as activation of
resident macrophages and dendritic cells.
In the setting of chronic inflammation, accumulation of growth
factors and products of chronic oxidation contribute to
irreversible tissue damage, including fibrosis/sclerosis, in
glomeruli, arteries, brain, lungs, and other tissues.

SLE is a multigenic disease.

Rare single-gene defects confer high hazard ratios (HR)
for SLE (525), including homozygous deficiencies of
early components of complement (C1q,r,s; C2; C4) and a
mutation in TREX1 on the X chromosome.
In most genetically susceptible individuals, normal
alleles of multiple genes each contribute a small amount
to abnormal immune/inflammation/tissue damage
responses; if enough predisposing variations are present,
disease results.
Thirty to forty predisposing genes have been identified in
recent genome-wide association studies in thousands of
Northern European white patients and controls. They
confer HR for SLE of 1.53. Such relatively weak gene
polymorphisms that increase risk for SLE can be
classified by their potential role in pathogenesis

Female sex is permissive for SLE with evidence for

hormone effects, genes on the X chromosome, and
epigenetic differences between genders playing a role.
Females of many mammalian species make higher
antibody responses than males. Women exposed to
estrogen-containing oral contraceptives or
hormone replacement have an increased risk of
developing SLE (1.22-fold).
Estradiol binds to receptors on T and B lymphocytes,
increasing activation and survival of those cells, thus
favoring prolonged immune responses. Genes on the X
chromosome that influence SLE, such as TREX-1, may
play a role in gender predispositionpossibly because
some genes on the second X in females are not silent.
People with XXY karyotype (Klinefelter's syndrome)
have a significantly increased risk for SLE.

PATHOLOGY

In SLE, biopsies of affected skin show deposition of

Ig at the dermal-epidermal junction (DEJ), injury to
basal keratinocytes, and inflammation dominated by
T lymphocytes in the DEJ and around blood vessels
and dermal appendages. Clinically unaffected skin
may also show Ig deposition at the DEJ.
In renal biopsies, the pattern and severity of injury
are important in diagnosis and in selecting the best
therapy.
Many clinical studies of lupus nephritis have used
the World Health Organization (WHO) classification
of lupus nephritis. However, the International
Society of Nephrology (ISN) and the Renal
Pathology Society (RPS) have published a newer,
similar classification (Table 319-2) that is replacing
WHO standards.

An advantage of the ISN/RPS classification is the

addition of "a" for active and "c" for chronic changes,
giving the physician information regarding the
potential reversibility of disease.
All the classification systems focus on glomerular
disease, although the presence of tubular interstitial
and vascular disease is important to clinical outcomes.
In general, class III and IV disease, as well as class V
accompanied by III or IV disease, should be treated
with aggressive immunosuppression if possible,
because there is a high risk for end-stage renal disease
(ESRD) if patients are untreated or undertreated.
Treatment for lupus nephritis is not recommended in
patients with class I or II disease or with extensive
irreversible changes. In children, a diagnosis of SLE
can be established on the basis of renal histology
without meeting additional diagnostic criteria

DIAGNOSIS

The diagnosis of SLE is based on characteristic clinical

features and autoantibodies.
Current criteria for classification are listed in Table 319-3, and
an algorithm for diagnosis and initial therapy is shown in Fig.
319-2.
The criteria are intended for confirming the diagnosis of SLE in
patients included in studies; the author uses them in individual
patients for estimating the probability that a disease is SLE.
Any combination of 4 of 11 criteria, well documented at any
time during an individual's history, makes it likely that the
patient has SLE. (Specificity and sensitivity are 95% and 75%,
respectively.)
In many patients, criteria accrue over time. Antinuclear
antibodies (ANA) are positive in >98% of patients during the
course of disease; repeated negative tests suggest that the
diagnosis is not SLE, unless other autoantibodies are present
(Fig. 319-2).

> 4 SLE

INTERPRETATION OF CLINICAL
MANIFESTATIONS
When a diagnosis of SLE is made, it is important
to establish the severity and potential
reversibility of the illness and to estimate the
possible consequences of various therapeutic
interventions.
In the following sections, descriptions of some
disease manifestations begin with relatively mild
problems and progress to those more lifethreatening.

OVERVIEW AND SYSTEMIC

MANIFESTATIONS
At its onset, SLE may involve one or several organ systems; over
time, additional manifestations may occur
Most of the autoantibodies characteristic of each person are
present at the time clinical manifestations appear (Tables 319-1
and 319-3).
Severity of SLE varies from mild and intermittent to severe and
fulminant.
Most patients experience exacerbations interspersed with
periods of relative quiescence; permanent complete remissions
(absence of symptoms with no treatment) are rare.
Systemic symptoms, particularly fatigue and
myalgias/arthralgias, are present most of the time. Severe
systemic illness requiring glucocorticoid therapy can occur with
fever, prostration, weight loss, and anemia with or without other
organ-targeted manifestations.

MUSCULOSKELETAL
MANIFESTATIONS
Most people with SLE have intermittent polyarthritis, varying
from mild to disabling, characterized by soft tissue swelling and
tenderness in joints, most commonly in hands, wrists, and knees.
Joint deformities (hands and feet) develop in only 10% of patients.
Erosions on joint x-rays are rare; their presence suggests a nonlupus inflammatory arthropathy such as rheumatoid arthritis;
some experts think that erosions can occur in SLE.
If pain persists in a single joint, such as knee, shoulder, or hip, a
diagnosis of ischemic necrosis of bone should be considered,
particularly if there are no other manifestations of active SLE.
The prevalence of ischemic necrosis of bone is increased in SLE,
especially in patients treated with systemic glucocorticoids.
Myositis with clinical muscle weakness, elevated creatine kinase
levels, positive MRI scan, and muscle necrosis and inflammation
on biopsy can occur, although most patients have myalgias without
frank myositis

CUTANEOUS MANIFESTATIONS

Lupus dermatitis can be classified as discoid lupus

erythematosus (DLE), systemic rash, subacutecutaneous lupus
erythematosus (SCLE), or "other."
Discoid lesions are roughly circular with slightly raised, scaly
hyperpigmented erythematous rims and depigmented, atrophic
centers in which all dermal appendages are permanently
destroyed.
Lesions can be disfiguring, particularly on the face and scalp.
Treatment consists primarily of topical or locally injected
glucocorticoids and systemic antimalarials.
Only 5% of people with DLE have SLE (although one-half have
positive ANA); however, among individuals with SLE, as many as
20% have DLE.
The most common SLE rash is a photosensitive, slightly raised
erythema, occasionally scaly, on the face (particularly the cheeks
and nosethe "butterfly" rash), ears, chin, V region of the neck
and chest, upper back, and extensor surfaces of the arms.

RENAL MANIFESTATIONS

Nephritis is usually the most serious manifestation of SLE,

particularly since nephritis and infection are the leading causes
of mortality in the first decade of disease.
Since nephritis is asymptomatic in most lupus patients,
urinalysis should be ordered in any person suspected of having
SLE.
The classification of lupus nephritis is primarily histologic.
Renal biopsy is useful in planning current and near-future
therapies.
Patients with dangerous proliferative forms of glomerular
damage (ISN III and IV) usually have microscopic hematuria and
proteinuria (>500 mg per 24 h); approximately one-half develop
nephrotic syndrome, and most develop hypertension.
If diffuse proliferative glomerulonephritis (DPGN) is untreated,
virtually all patients develop ESRD within 2 years of diagnosis.
Therefore, aggressive immunosuppression is indicated (usually
systemic glucocorticoids plus a cytotoxic drug), unless 90% of
glomeruli have irreversible damage

Mesangial proliferative lupus nephritis with moderate

mesangial hypercellularity.
From International Society of Nephrology/Renal Pathology
Society 2003 class II (200, hematoxylin-eosin).

NERVOUS SYSTEM MANIFESTATIONS

There are many central nervous system (CNS) and

peripheral nervous system manifestations of SLE; in some
patients these are the major cause of morbidity and
mortality.
It is useful to approach this diagnostically by asking first
whether the symptoms result from SLE or another condition
(such as infection in immunosuppressed individuals).
If symptoms are related to SLE, it should be determined
whether they are caused by a diffuse process (requiring
immunosuppression) or vascular occlusive disease (requiring
anticoagulation).
The most common manifestation of diffuse CNS lupus is
cognitive dysfunction, including difficulties with memory and
reasoning.
Headaches are also common

This axial, T2-weighted

brain magnetic resonance
image (MRI)
demonstrates an area of
ischemia in the right
periventricular white
matter of a 41-year-old
woman with longstanding systemic lupus
erythematosus (SLE).
She presented with
headache and subtle
cognitive impairments
but no motor deficits.

VASCULAR OCCLUSIONS

The prevalence of transient ischemic attacks, strokes, and myocardial

infarctions is increased in patients with SLE.
These vascular events are increased in, but not exclusive to, SLE patients
with antibodies to phospholipids (aPL).

Antiphospholipid antibodies are associated with hypercoagulability and

acute thrombotic events, whereas chronic disease is associated with
accelerated atherosclerosis.
Ischemia in the brain can be caused by focal occlusion (either
noninflammatory or associated with vasculitis) or by embolization from
carotid artery plaque or from fibrinous vegetations of Libman-Sacks
endocarditis.
Appropriate tests for aPL and for sources of emboli should be ordered in
such patients to estimate the need for, intensity of, and duration of antiinflammatory and/or anticoagulant therapies.
In SLE, myocardial infarctions are primarily manifestations of accelerated
atherosclerosis

PULMONARY MANIFESTATIONS

The most common pulmonary manifestation of SLE is

pleuritis with or without pleural effusion.

This manifestation, when mild, may respond to treatment

with nonsteroidal anti-inflammatory drugs (NSAIDs); when
more severe, patients require a brief course of glucocorticoid
therapy.
Pulmonary infiltrates also occur as a manifestation of active
SLE and are difficult to distinguish from infection on
imaging studies.
Life-threatening pulmonary manifestations include
interstitial inflammation leading to fibrosis, shrinking lung
syndrome, and intra-alveolar hemorrhage; all of these
probably require early aggressive immunosuppressive
therapy as well as supportive care.

CARDIAC MANIFESTATIONS
Pericarditis is the most frequent cardiac manifestation; it
usually responds to anti-inflammatory therapy and infrequently
leads to tamponade.
More serious cardiac manifestations are myocarditis and fibrinous
endocarditis of Libman-Sacks.
The endocardial involvement can lead to valvular insufficiencies,
most commonly of the mitral or aortic valves, or to embolic events.
It has not been proven that glucocorticoid or other
immunosuppressive therapies lead to improvement of lupus
myocarditis or endocarditis, but it is usual practice to administer a
trial of high-dose steroids along with appropriate supportive
therapy for heart failure, arrhythmia, or embolic events. As
discussed above, patients with SLE are at increased risk for
myocardial infarction, usually due to accelerated atherosclerosis,
which probably results from immune attack, chronic
inflammation, and/or chronic oxidative damage to arteries.

HEMATOLOGIC MANIFESTATIONS
The most frequent hematologic manifestation of SLE is
anemia, usually normochromic normocytic, reflecting
chronic illness.
Hemolysis can be rapid in onset and severe, requiring highdose glucocorticoid therapy, which is effective in most
patients.
Leukopenia is also common and almost always consists of
lymphopenia, not granulocytopenia; this rarely predisposes
to infections and by itself usually does not require therapy.
Thrombocytopenia may be a recurring problem. If platelet
counts are >40,000/L and abnormal bleeding is absent,
therapy may not be required. High-dose glucocorticoid
therapy (e.g., 1 mg/kg per day of prednisone or equivalent)
is usually effective for the first few episodes of severe
thrombocytopenia

GASTROINTESTINAL
MANIFESTATIONS
Nausea, sometimes with vomiting and diarrhea, can be
manifestations of an SLE flare, as can diffuse abdominal
pain probably caused by autoimmune peritonitis and/or
intestinal vasculitis.
Increases in serum aspartate aminotransferase (AST)
and alanine aminotransferase (ALT) are common when
SLE is active.
These manifestations usually improve promptly during
systemic glucocorticoid therapy.
Vasculitis involving the intestine may be life-threatening;
perforations, ischemia, bleeding, and sepsis are frequent
complications. Aggressive immunosuppressive therapy
with high-dose glucocorticoids is recommended for shortterm control; evidence of recurrence is an indication for
additional therapies

OCULAR MANIFESTATIONS
Sicca syndrome (Sjgren's syndrome); and nonspecific
conjunctivitis are common in SLE and rarely threaten
vision.
In contrast, retinal vasculitis and optic neuritis are
serious manifestations: blindness can develop over
days to weeks.
Aggressive immunosuppression is recommended,
although there are no controlled trials to prove
effectiveness. Complications of glucocorticoid therapy
include cataracts (common) and glaucoma

LABORATORY TESTS

(1) to establish or rule out the diagnosis;

(2) to follow the course of disease, particularly to
suggest that a flare is occurring or organ damage
is developing; and
(3) to identify adverse effects of therapies.

TESTS FOR AUTOANTIBODIES

Diagnostically, the most important autoantibodies to detect
are ANA as the test is positive in >95% of patients, usually at
the onset of symptoms. A few patients develop ANA within 1
year of symptom onset; repeated testing may thus be useful.
ANA-negative lupus exists but is rare in adults and is usually
associated with other autoantibodies (anti-Ro or anti-DNA).
High-titer IgG antibodies to double-stranded DNA (dsDNA)
(but not to single-stranded DNA) are specific for SLE.
There is no international standardized test for ANA;
variability between different service laboratories is high.
Enzyme-linked immunosorbent assays (ELISA) and
immunofluorescent reactions of sera with the dsDNA in the
flagellate Crithidia luciliae have 60% sensitivity for SLE;
identification of high-avidity anti-dsDNA in the Farr assay is
not as sensitive but may correlate better with risk for
nephritis

Titers of anti-dsDNA vary over time. In some patients, increases

in quantities of anti-dsDNA herald a flare, particularly of
nephritis or vasculitis, especially when associated with declining
levels of C3 or C4 complement.
Antibodies to Sm are also specific for SLE and assist in
diagnosis; anti-Sm antibodies do not usually correlate with
disease activity or clinical manifestations.
aPL are not specific for SLE, but their presence fulfills one
classification criterion, and they identify patients at increased
risk for venous or arterial clotting, thrombocytopenia, and fetal
loss.
There are two widely accepted tests that measure different
antibodies (anticardiolipin and the lupus anticoagulant): (1)
ELISA for anticardiolipin (internationally standardized with good
reproducibility) and (2) a sensitive phospholipid-based activated
prothrombin time such as the dilute Russell venom viper test.
Some centers also recommend measurement of antibodies to 2
glycoprotein 1, a serum protein cofactor that is the target of most
antibodies to cardiolipin and some lupus anticoagulants.

TREATMENT:
SYSTEMIC LUPUS
ERYTHEMATOSUS

There is no cure for SLE, and complete sustained

remissions are rare. Therefore, the physician should
plan to induce improvement of acute flares and then
maintain improvements with strategies that suppress
symptoms to an acceptable level and prevent organ
damage.
Usually patients will endure some adverse effects of
medications.
Therapeutic choices depend on (1) whether disease
manifestations are life-threatening or likely to cause
organ damage, justifying aggressive therapies; (2) whether
manifestations are potentially reversible; and (3) the best
approaches to preventing complications of disease and its
treatments

CONSERVATIVE THERAPIES FOR

MANAGEMENT OF NON-LIFE-THREATENING
DISEASE
Among patients with fatigue, pain, and autoantibodies of SLE,
but without major organ involvement, management can be
directed to suppression of symptoms.
Analgesics and antimalarials are mainstays.
NSAIDs are useful analgesics/anti-inflammatories, particularly
for arthritis/arthralgias.
However, two major issues currently indicate caution in using
NSAIDs. First, SLE patients compared with the general
population are at increased risk for NSAID-induced aseptic
meningitis, elevated serum transaminases, hypertension, and
renal dysfunction. Second, all NSAIDs, particularly those that
inhibit cyclooxygenase-2 specifically, may increase risk for
myocardial infarction.
Acetaminophen to control pain may be a good strategy,
but NSAIDs are more effective in some patients

Antimalarials (hydroxychloroquine, chloroquine, and

quinacrine) often reduce dermatitis, arthritis, and
fatigue.
A randomized, placebo-controlled, prospective trial has
shown that withdrawal of hydroxychloroquine results in
increased numbers of disease flares. Hydroxychloroquine
reduces accrual of tissue damage over time.
Because of potential retinal toxicity, patients receiving
antimalarials should undergo ophthalmologic
examinations annually.
A placebo-controlled prospective trial suggests that
administration of dehydroepiandrosterone may reduce
disease activity.
If quality of life is inadequate in spite of these
conservative measures, treatment with low doses
of systemic glucocorticoids may be necessary.

MEDICATIONS FOR THE

MANAGEMENT OF SLE

PATIENT OUTCOMES,
PROGNOSIS, AND
SURVIVAL

Survival in patients with SLE in the United States,

Canada, Europe, and China is approximately 95% at 5
years, 90% at 10 years, and 78% at 20 years.
In the United States, African Americans and Hispanic
Americans with a mestizo heritage have a worse
prognosis than whites, whereas Africans in Africa and
Hispanic Americans with a Puerto Rican origin do not.
The relative importance of gene mixtures and
environmental differences accounting for ethnic
differences is not known.
Poor prognosis (50% mortality in 10 years) in most
series is associated with (at the time of diagnosis) high
serum creatinine levels [>124 mol/L (>1.4 mg/dL)],
hypertension, nephrotic syndrome (24-h urine protein
excretion >2.6 g), anemia [hemoglobin <124 g/L (<12.4
g/dL)], hypoalbuminemia, hypocomplementemia, aPL,
male sex, and ethnicity (African American, Hispanic
with mestizo heritage).

Data regarding outcomes in SLE patients with renal

transplants show mixed results: some series have a twofold
increase in graft rejection compared to patients with other
causes of ESRD, whereas others show no differences. Overall
patient survival is comparable (85% at 2 years).
Lupus nephritis occurs in approximately 10% of
transplanted kidneys.
Disability in patients with SLE is common due primarily to
chronic fatigue, arthritis, and pain, as well as renal disease.
As many as 25% of patients may experience remissions,
sometimes for a few years, but these are rarely permanent.
The leading causes of death in the first decade of
disease are systemic disease activity, renal failure,
and infections; subsequently, thromboembolic events
become increasingly frequent causes of mortality.