Systemic Lupus

Erythematosus

EPIDEMIOLOGY
SLE is a disease that can affect persons of all ages and ethnic groups
and both sexes, but more than 90% of new patients presenting with
SLE are women in the childbearing years. The reported prevalence
of SLE is 20-150 per 100,000. In the United States, data from states
with large urban populations indicated the prevalence was 104-170
per 100,000 women.1 This gender disparity is not as prominent in
early life (<20 years of age) and later in life (>40 years of age).2
The LUMINA (Lupus in Minority population, Nature versus
nurture) cohort is providing a more generalizable database for the
epidemiology of SLE. LUMINA is a longitudinal outcome study of
patients with SLE. This study does not include patients younger than
17 years. Among the LUMINA cohort, 90% of SLE patients are
female, 44% are African American, 23% are Latin American, and
32% are white.3 Based on 2004 data from the National Health and
Nutrition Examination Survey (NHANES), the prevalence of SLE
patients receiving treatment was 100 per 100,000 among American
women.4
Although patients with SLE almost uniformly present with a
positive antinuclear antibody (ANA) test, other conditions exhibit
positive ANAs as well. Craig and colleagues found an ANA titer of
1:64 or greater in 15% of healthy women younger than 40 years and
in 24% of women older than 40 years.5 The American College of
Rheumatology criteria for SLE ensure uniformity of patients in
research studies.

PATHOPHYSIOLOGY
Patients with SLE have a complex array of abnormalities involving
their immune system. Twin studies and genetic linkage studies
suggest that heredity plays a role in the development of lupus.6
Many biochemical studies have revealed abnormalities in T cell function, B cell function, programmed cell death (apoptosis), immune
complex clearance, complement function and deficiencies, and
nucleosome processing.7,8 In general, these studies support an abnormal functioning immune system. It is still not clear exactly what
starts the immune dysregulation, but it does appear to require a
genetically susceptible host affected by either a exogenous trigger or
an endogenous metabolic disturbance that causes the loss of tolerance to self antigen.9,10
Different ethnic groups have different genetic abnormalities; for
example, east Asians with SLE have more cytotoxic T lymphocyte
antigen-4 (CTLA-4), and whites with lupus nephritis have more
abnormalities in Fc- receptors.11,12 In the future, a specific genetic

and immunity-based diagnosis may be given, such as T cell protein

kinase type I deficiency.13
The majority of the pathology in lupus is related to deposits of
immune complex. The immune complexes deposit in various organs,
which triggers complement and other mediators of inflammation.
Autoantibodies in SLE are directed against a wide variety of self
antigens. Autoantibodies directed against nuclear self antigen (ANA)
are the most characteristic of SLE.13 Commonly found target nuclear
antigens in SLE include native DNA, denatured DNA, histone,
Smith, U1 ribonuclear protein (RNP), SSA, SSB, and ribosomal
RNP. Among these, double-stranded DNA (dsDNA) and Smith
appear to be unique to SLE. Therefore, it can be helpful, in diagnosing SLE, to look for these more-specific autoantibodies to help in
establishing the diagnosis.

CLINICAL PRESENTATION
Constitutional
SLE can affect any of the major organ systems. As its name implies,
SLE can also have systemic or constitutional symptoms. These symptoms can mimic other autoimmune diseases, infectious diseases,
endocrine abnormalities, chronic fatigue, and fibromyalgia. Because
the general symptoms are not specific, it is important to use them
along with more organ-specific symptoms that can help differentiate
lupus from other diseases. Common symptoms elicited by history
include fever, fatigue, weight loss, myalgia, and arthralgia. There are
many reports of these nonspecific symptoms with or without rash
occurring after sun exposure.

Dermatologic
Lupus was first described as a dermatologic condition. The SLE
patient often presents to a physician when the cutaneous manifestations occur. Because of the photosensitive nature of the rash, the
prevalence of rash in SLE depends on the region of the world in
which the patient lives. It is also important to remember that lupus
can be limited to the integumentary system. Box 1 lists the common
forms of lupus when it involves the skin.
Red plaques that occur on sun-exposed areas of the body characterize acute cutaneous lupus. Acute cutaneous lupus can have associated alopecia, but the rash and hair loss do not lead to scarring. The
malar or butterfly rash is the best-known manifestation of acute
cutaneous lupus. The malar rash spares the nasolabial folds; the body
of the butterfly is separate from its wings.
Discoid lesions can also occur in systemic lupus but are not as
common as the acute cutaneous lupus rash. Discoid lesions are often
scarring. The rash of subacute cutaneous lupus often appears as
annular rings with crusted margins and spares the mid face. Lupus
panniculitis manifests as a deeper rash that is often tender; it can look
like erythema nodosum, which is another type of panniculitis. SLE
can manifest with a vasculitic type of rash: palpable purpura or
pernio. Pernio is an erythematous, often painful area at the tip of a
digit seen after cold exposure.
The oral and nasal ulcers of systemic lupus are classically described
as painless; however, these lesions may be quite painful. Oral involve-

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Systemic lupus erythematosus (SLE) is a prototypic autoimmune

disease that has a broad range of clinical manifestations. In SLE,
tissue damage in multiple organs is caused by autoantibodies
and immune complexes. Because other autoimmune diseases, infectious diseases, central nervous system diseases, and fibromyalgia
can also manifest with multisystem disease involvement, these other
conditions need to be considered when considering a diagnosis
of SLE.

Abby Abelson

DEFINITION

and

S E C T I O N 13

Bridget Wright, Swati Bharadwaj,

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Box 1 Common Forms of Cutaneous Lupus

Box 2 Findings in Patients with SLE-Related Pleural Effusion

Acute cutaneous lupus

Chronic or discoid lupus
Lupus panniculitis
Lupus pernio
Subacute cutaneous lupus
Tumid lupus

Lupus pleuritis or pleural effusions

Exudate
Normal glucose (low in rheumatoid arthritis)
White blood cell count moderately increased
Polymorphonuclear predominance early
Lymphocyte predominance late
Antinuclear antibodies
Negative cultures

ment most commonly affects the posterior aspect of the hard palate.
The nasal and oral ulcers usually are recurrent or chronic. Mucous
membrane involvement can also involve the vagina. Young sexually
active women should be evaluated with this in mind.

Musculoskeletal
The most common initial manifestation of SLE is arthralgia or arthritis,14 with a frequency of 48% in patients followed for 10 years.15
Arthralgia, expressed by the patient as pain and stiffness, is more
common than objective arthritis. The arthritis in SLE can be migratory and transient; it may be present at the time the patient makes
the appointment but resolved by the time of the evaluation. Arthritis
in SLE tends to have fewer erosions and fixed deformities compared
with rheumatoid arthritis.
There is a clinical condition described as rhupus. These patients
have a rheumatoid arthritis-like presentation along with other characteristics of lupus; this is a rare entity, but one that should be kept
in mind. Periarticular inflammation is more common in lupus. This
periarticular inflammation often involves the tendon sheaths and can
lead to Jaccouds arthropathy. Jaccouds arthropathy involves swanneck deformities of the fingers, which are reducible.16,17
Muscle disease is fairly common in SLE. These patients often
present with myalgia complaints, and the cause of these muscle pains
is not always clear. Again, it is important to recognize that SLE
patients often have coexisting fibromyalgia complaints related to
chronic disease, poor sleep, inactivity, and depression or mood problems. Some SLE patients have myositis that can be proved by biopsy.
The frequency of myositis in lupus patients is approximately 4%. The
biopsy is often similar to polymyositis. If myositis is suspected by
elevations in the creatine kinase without specific muscle weakness,
magnetic resonance imaging (MRI) of the gluteal and upper thigh
muscles can be used to look for an abnormal signal, which might
lead to a potential biopsy site. It is important to distinguish nonspecific myalgia from myositis, because treatment could be affected.
Osteonecrosis is an important musculoskeletal component of
SLE. It can manifest as acute joint pain in patients with advanced
disease or during periods of high-dose corticosteroid use. Retrospective studies have shown that higher doses of corticosteroids in the
first 6 to 18 months of treatment are associated with osteonecrosis.18,19 Duration of treatment or disease severity does not correlate
with the onset of osteonecrosis.18 It is important to investigate large
joint pain, particularly hip or knee pain, in a patient with SLE.
Because the beginning stages of osteonecrosis do not show changes
on plain film, MRI should be considered in patients with negative
plain films and persistent or unexplained pain. Osteonecrosis can be
debilitating, however, and early diagnosis with limited weight bearing
can prevent subsequent joint replacement in some.

Pulmonary
Serositis can affect both the cardiac and pulmonary systems, and
cardiac and pulmonary serositis often coexist. Most large studies on
the outcomes and frequency of particular manifestations of lupus
assess for serositis but not for specific types. In patients with lupus
followed for 10 years, pleural effusions occur in as many as 50% of
patients. These effusions are often small and bilateral but occasionally can be unilateral and quite large. Effusions are often accompa-

SLE, systemic lupus erythematosus.

nied by pleuritic chest pain. It is important to consider infection in

patients with newly diagnosed or longstanding SLE presenting with
pleural effusions. Box 2 reviews the results of pleural effusion evaluation in SLE.
Lupus patients can develop other forms of pulmonary disease
including shrinking lung, acute pneumonitis, chronic or fibrotic
pneumonitis, alveolar hemorrhage, pulmonary hypertension, and
thromboembolic-related disease. Shrinking lung is believed to be
related to diaphragmatic weakness and decreased chest wall compliance.20,21 Pulmonary function tests in these patients do not explain
the patients complaints of dyspnea, but chest radiographs reveal
bibasilar atelectasis and upward deviation of the diaphragm.
Acute pneumonitis has an abrupt onset with fever, cough, pleuritic chest pain, hemoptysis, and dyspnea. Pulmonary function tests
might reveal severe restriction, and pulmonary infiltrates are seen on
chest radiography.22 The incidence of acute pneumonitis is not clear,
but Matthay observed an incidence of 11.7% in his SLE population.22
Infectious causes must always be ruled out in these patients before
the diagnosis of acute lupus pneumonitis is entertained. This workup
usually requires bronchoscopy with cultures. Biopsies consistent
with lupus pneumonitis reveal acute alveolar injury with edema,
hyaline membrane formation, and perivascular inflammation.23 It
has been noted that a higher-than-expected percentage of lupus
patients with pneumonitis are positive for SSA.24
Chronic pneumonitis is an insidious form of lung involvement
with progressive dyspnea and diffuse interstitial lung infiltrates on
plain chest radiography. Pulmonary function testing shows a restrictive pattern with decreased diffusion capacity. The incidence of
chronic lung involvement in lupus is less than 10%.25
Pulmonary vascular involvement in lupus is also observed. This
includes diffuse alveolar hemorrhage, thromboembolic disease, and
pulmonary hypertension. Diffuse alveolar hemorrhage is an emergency manifesting with sudden-onset shortness of breath, dropping
hemoglobin, and diffuse infiltrates on chest radiography. Although
hemoptysis generally occurs at some point in this illness, less than
one half of patients presenting with lupus-related alveolar hemorrhage have this symptom. Bronchoscopy can demonstrate red blood
cells and hemosiderin-laden macrophages. These patients require
high-dose corticosteroids.
Thromboembolic disease associated with antiphospholipid antibodies can lead to acute pulmonary embolism with acute pulmonary
hypertension. Chronic small pulmonary embolisms can be associated with this disease and lead to slowly worsening pulmonary hypertension. Pulmonary hypertension can develop as a sequela from
thromboembolic lung disease, but it can also be primary (cor pulmonale). It is important to keep this in mind, especially in patients
with breathlessness, normal oximetry, and normal chest radiography, because an echocardiogram can indicate the diagnosis.

Cardiac
Cardiac involvement occurs in 20% to 30% of patients with SLE. It
is most common in Latin Americans, followed by African Americans,
then whites.26 Pericardial effusions are seen in about 20% of patients
with SLE; however, more than 50% are found to have effusions on

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Lupus nephritis is a common and potentially devastating manifestation of lupus. Renal disease in lupus is associated with significant
morbidity and mortality. In general, lupus nephritis occurs in more
than half of SLE patients. However, there is a disparity between
nephritis in Latin Americans and African Americans compared with
whites. The incidence of nephritis is 60% for Latin Americans, 69%
for African Americans, and 29% for whites.32
Although nephritis can occur during a flare of SLE with skin
manifestations or other organ system involvement, it often occurs
without other clinical signs of active lupus. Thus, it is of key importance that patients with lupus have routine urine analysis with
microscopy looking for protein, blood, and cellular casts. Patients can
present with constitutional symptoms including fatigue, weight loss,
and fever, as well as hypertension and edema, but generally patients
do not develop symptoms until late in the disease process of nephritis.
Lupus nephritis is primarily caused by the deposition of immune
complexes. The size of the complexes determines the location of
deposition and therefore leads to differences in classification (mesangial, focal, diffuse).33 Once deposited, the immune complexes can set
off the complement cascade, producing cellular damage and chemoattractants (C3a and C5a), leading to further recruitment of
inflammatory cells. Immune complexes also can lead to upregulation
of adhesion molecules on endothelial cells, leading to recruitment of
immune cells such as macrophages and T cells, which in turn produce
cytokines. Damaged glomerular cells also can produce cytokines that
lead to further increase in the inflammatory infiltration.33-35
The classification of lupus nephritis is based on renal biopsy. The
specific class does give helpful information regarding outcomes and
specific therapeutic regimens. If possible, a biopsy should be obtained
on any patient in whom renal involvement in suspected. Although
there are studies looking at the presence of renal abnormalities in
patients with no suspected renal involvement, renal biopsy need not
be done routinely on patients with normal creatinine values and
normal urine analysis. The 2003 revision of the classification of glomerulonephritis in SLE divides the disease process into six classes,
with subdivisions of classes III and IV (Box 3).
The primary complication of lupus nephritis is permanent renal
damage. This damage may be severe enough that it leads to renal
failure and dependence on dialysis. All of the complications associated with renal failure apply to these patients, such as hypertension,
fluid overload, premature vascular calcifications, hyperlipidemia,
and premature coronary artery disease.

Gastrointestinal
GI effects from SLE are not clearly defined. SLE can involve any
part of the GI tract as a result of disease activity or side effects of
medications.36

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Raynauds phenomenon occurs in one third of patients at the onset

of SLE, and more than one half develop it during the course of their
disease. Unlike Raynauds phenomenon in systemic sclerosis, patients
with lupus rarely develop ischemic digits or digital ulcers. Raynauds
phenomenon can affect the fingers, toes, ears, nose, and even the
tongue. It is often triggered by cold, cigarette smoke, caffeine, overthe-counter cold medications, and stress. Livedo reticularis also is
commonly seen in lupus patients and is due to spasm of the dermal
ascending arterioles.
Venous thromboembolism is known to be associated with
antiphospholipid antibody syndrome, which can coexist with SLE.

Renal

Vascular

However, venous thromboembolism is also increased in lupus

patients who have a history of smoking at the time of diagnosis,
increased disease activity over time, increased mean dose of glucocorticoids, shorter disease duration at the time of diagnosis, and
presence of lupus anticoagulant.31
Lupus patients can also develop inflammatory vascular disease in
the form of vasculitis. It is difficult to estimate the incidence of vasculitis in lupus because reporting has been mainly in the form of case
reports or series, and the diagnosis of vasculitis is often based on
clinical acumen without biopsy-proven vasculitis. Vasculitis in SLE
is due to a complex interplay between immune cells, endothelial cells,
deposition of autoantibodies, and immune complex deposition. In
addition to reports of small- and medium-vessel vasculitis involving
all the major organs including the skin, gastrointestinal (GI), pulmonary, cardiac, and genitourinary systems, there are reports of vasculitis affecting the placenta, leading to fetal mortality. There have also
been case reports of SLE and Takaysus arteritis.

S E C T I O N 13

autopsy. When symptoms do occur, they include precordial chest

pain, which is worse with lying down and relieved with leaning
forward. A pericardial rub can often be heard on clinical examination. Many patients with clinically silent disease are found to have
pericardial effusions when enlarged cardiac silhouette is seen on
chest radiography, fluid is found on computed tomography (CT) of
the chest, or echocardiogram obtained for other reasons reveals effusion. It is unusual (<1%) for pericardial effusions related to lupus to
progress to tamponade.27 However, when pericardiocentesis has been
necessary, the fluid reveals leukocytosis with neutrophil predominance, low glucose, reduced complement levels, low complement
activity, and positive ANA.27 Pericardial and pleural effusions usually
respond to corticosteroid therapy.
Valvular involvement in lupus is common and often asymptomatic. The mitral valve is involved most often. Mitral valve prolapse
has been observed in 25% of lupus patients as opposed to 9% of
controls.28 Valvular abnormalities in lupus include vegetations,
regurgitation, and valvular stenosis. Because stroke, peripheral
embolism, heart failure, death, and infective endocarditis can be
associated with valvular abnormalities, cardiac auscultation and palpation should be done routinely. If abnormalities or changes from
previous examination are noted, further investigation with echocardiography should be pursued.
Verrucous endocarditis is also common in SLE. Verrucae consist
of immune complexes, mononuclear cells, fibrin, and platelet
thrombi. In a study using transesophageal echocardiography, 43% of
SLE patients were found to have verrucous lesions. Scarring and
valve deformation can occur subsequent to the healing of these
lesions. These lesions are often asymptomatic; however, awareness
of these lesions is important because they can produce emboli or
become secondarily infected.
Myocarditis also can occur in SLE but is uncommon. It should
be suspected if there is resting tachycardia. Myocarditis can lead to
global cardiac dysfunction as well as electrophysiologic abnormalities. Myocardial biopsy may be needed in cases where acute myocarditis is suspected versus fibrosis or myocardial infarction. Treatment
for acute myocarditis requires high-dose glucocorticoids plus additional immunosuppression.
Coronary artery disease (CAD) has been recognized in several
studies to be increased in patients with SLE compared with the general
population, even when traditional cardiac risk factors are eliminated.
Important risk factors in lupus patients include use of glucocorticoids, chronic nephritis, antiphospholipid antibodies,29 and increased
oxidative stress.30 It is important to be aware of the increased incidence of CAD, especially because SLE often affects young women who
are traditionally not thought to be at high risk for CAD. Any traditional risk factors for CAD such as smoking, inactivity, obesity, and
elevated cholesterol should be addressed in this population. Hypertension should be aggressively controlled, which can be difficult in
patients with underlying renal disease. In addition, since women with
SLE have a 7- to 50-fold increased risk of CAD, which can lead to
significant morbidity and premature death, a high index of suspicion
is warranted when SLE patients present with dyspnea, chest pain,
chest pressure, decreased exercise tolerance, or atypical symptoms.

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Box 3 International Society of Nephrology/Renal Pathology

Society (ISN/RPS) 2003 Classification of Lupus Nephritis

to SLE.40 Treatment of acute abdominal pain is directed at the cause,

with appropriate medical or surgical management of the presenting
manifestation.

Class I: Minimal mesangial lupus nephritis

Class II: Mesangial proliferative lupus nephritis
Class III: Focal lupus nephritis

Intestines

III (A): active lesions

III (A/C): active and chronic lesions
III (C): chronic lesions

Class IV: Diffuse lupus nephritis (50% of glomeruli)

Diffuse segmental (IV-S) or global (IV-G) lupus nephritis

IV (A): active lesions
IV (A/C): active and chronic lesions
IV (C): chronic lesions

Class V: Membranous lupus nephritis

Class VI: Advanced sclerosing lupus nephritis (90% globally sclerosed
glomeruli without residual activity)

Oral Cavity
About one half of patients with systemic lupus have oral ulcers that
are usually painful if discoid and painless if erythematous. They tend
to be located on the hard palate, on the buccal mucosa, or along the
vermilion border.37 Oral ulcers are one of the nonspecific findings in
lupus and are by no means diagnostic of the disease itself. They can
support a diagnosis of lupus when present with other lupus symptoms and serologies. In a setting of established lupus they could
represent a disease flare, side effects of medications such as methotrexate, or an opportunistic infection. Treatment of oral ulcers is
directed at the cause and consists of controlling the disease activity,
administering folic or folinic acid (if they are caused by methotrexate), or treating the infection. Symptomatic treatment is directed at
relieving the pain with pain medications or local application of
crushed 1-mg prednisone tablets.
Esophagus
Lupus patients occasionally complain of dysphagia or odynophagia.
This can be multifactorial from hypomotility,38 from reflux disease,
or from candidiasis from immunosuppression. If the symptoms are
severe, they deserve a regular dysphagia evaluation with motility
studies, x-rays, and maybe an endoscopy. Although treatment is
directed at the cause, motility drugs are no longer favored due to
their arrythmogenic potential. Antireflux medications or antifungals
are used when appropriate.
Abdomen
Abdominal pain is a diagnostic challenge in SLE and is probably one
of the most clinically threatening GI manifestation to be aware
of. Min and colleagues looked at causes of acute abdominal pain in
SLE patients in emergency departments (EDs). They documented
that 59.1% of visits to the ED by SLE patients were from pain due
to ischemic bowel disease.39 The other causes were splenic infarcts,
renal venous thrombosis, pancreatitis, serositis, upper GI bleeds,
pelvic inflammatory disease, and ectopic pregnancy. Peptic ulcer
disease with perforation also manifested as an acute abdomen in a
small number of patients with SLE and concomitant NSAID use.37
Medina and colleagues emphasized the importance of early laparotomy in SLE patients with higher SLE disease activity index
(SLEDAI) scores and acute abdominal pain. They studied the relation between SLEDAI scores and sources of an acute abdomen in 51
SLE patients and found that patients with intra-abdominal vasculitis
(19) or thrombosis (3) had higher SLEDAI scores than 14 patients
who had active SLE with non-SLE-related acute abdomen. Fifteen
patients with inactive SLE had intra-abdominal pathology unrelated

In the bowel, SLE can manifest with vasculitis, malabsorption, or

dysmotility.37 Mesenteric vasculitis in lupus can manifest as an acute
abdomen with fever, nausea, vomiting, diarrhea, and rectal bleeding
or with the characteristic mesenteric ischemic pain related to meals.
The mesenteric involvement can be attributed to either a lupus flare
or antiphospholipid antibodies. Suspicion based on a clinical, angiographic, or CT examination of mesenteric vasculitis without bowel
perforation warrants an evaluation by a rheumatologist and a possible aggressive therapeutic approach with intravenous steroids with
or without other cytotoxic agents, besides the routine treatments
with nothing by mouth, IV fluids, cultures, and broad-spectrum
antibiotics.41 If there is intestinal perforation from vasculitis, surgery
is the first option followed by cautious start of steroids and cytotoxic
agents in the postoperative period. Malabsorption in the form of a
protein-losing enteropathy in lupus is uncommon and manifests
with diarrhea, abdominal pain, and anasarca. The enteropathy might
respond to steroids with or without cytotoxic drugs.
Pancreas
Pancreatitis in lupus is uncommon and could occur in a setting of
high SLEDAI scores, antiphospholipid antibody syndrome, and
probable steroid use.37 The more likely causes, as in any other setting,
are gallstones, alcohol, and hypertriglyceridemia. Treatment is the
same as for pancreatitis from any other cause and includes nothing
by mouth, IV fluids, withholding causal drugs, and, rarely, use of
steroids if the cause is established by exclusion.
Liver
Drugs, viruses, fatty infiltration, or congestion have been implicated
as more common causes of liver enzyme abnormalities in SLE
patients.37 Hepatitis from lupus (lupus hepatitis), although uncommon, manifests as a mild elevation in liver enzymes (aspartate transaminase [AST], alanine transaminase [ALT)], lactate dehydrogenase
[LDH], alkaline phosphatase), usually in a setting of active lupus.
Such biochemical liver abnormalities from an SLE flare have a tendency to reverse with steroids. Lupoid hepatitis is a separate entity
and is considered a subset of chronic active autoimmune hepatitis,
where the liver is the main organ of involvement. Patients with lupus
hepatitis and lupoid hepatitis can have arthralgias, hypergammaglobulinemia, and positive ANAs.37 Serologic differentiation may be
possible at times and in general involves the presence of anti
ribosomal P and dsDNA autoantibodies in lupus hepatitis versus
antismooth muscle and autoliver-kidney-mitochondrial (LKM)
antibodies in lupoid hepatitis. Definite differentiation is only possible on histology, which shows a lobular involvement in lupus hepatitis versus rosetting of liver cells and dense lymphoid infiltrate in
lupoid hepatitis.

Neuropsychiatric
Neuropsychiatric SLE (NPSLE) could be defined as the neurologic
syndromes of the central, peripheral, and autonomic nervous systems
and the psychiatric syndromes observed in patients with SLE in
which other causes have been excluded.42,43 NPSLE has many diagnostic and prognostic implications. The American College of Rheumatology (ACR) committee has developed 19 NPSLE case definitions
with diagnostic criteria, exclusions, associations, and ascertainment,
as well as reporting standards. The complete case definitions are on
the ACR website (http://www.rheumatology.org). The proposed
pathologic mechanisms of NPSLE are highly complex and poorly

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understood. They could be vasculopathic (injury, infarcts, accelerated atherosclerosis, perivascular inflammation), occasionally
vasculitic, autoantibody mediated (antiphospholipid, antineuronal,
anti-RNP), steroid mediated, or biochemically mediated.

Neonatal Lupus
Neonatal lupus occurs in 1% to 2% of babies.54 At-risk babies are
those born to mothers with SLE, anti-Ro/SSA, and anti-La/SSB.
These babies are at risk for neonatal heart blocks, AV nodal damage
due to binding of antibodies, and, rarely, sinoatrial node damage.
They can have partial or complete heart blocks, bradycardia, and a
self-limited erythematous annular rash on the scalp and periorbital
area. Fetal bradycardia during routine fetal auscultation, ultrasound,
or echocardiogram in a high-risk mother should raise suspicion of
neonatal heart block. Other uncommon manifestations are transposition of the great vessels, ostium primum atrial septal defect, ventricular septal defect, endocardial fibroelastosis, and myocarditis.
Other systemic manifestations reported are hepatobiliary and hematologic.
Prenatal screening in high-risk mothers is important and guides
the use of fetal echocardiograms. Fetal echocardiograms are routinely done once a week in the second trimester and then every other
week until 32 weeks gestation.
A pediatric rheumatologist should be involved early. Fetal monitoring in high-risk pregnancies and postnatal monitoring in affected
babies are important. Incomplete heart block in the fetus tends to
respond to fluorinated glucocorticoids if started immediately and
continued until delivery. It is usually stopped if there is no response
in 4 to 6 weeks. A baby with complete heart block might need a
pacemaker.

Drug-Induced Lupus
Drug-induced lupus is epidemiologically, clinically, and serologically
different from SLE. The male-to-female distribution is equal and the
average age is 50 years. The most common drugs implicated are
isoniazid, hydralazine, and procainamide. Other drugs implicated
include minocycline, aldomet, diltiazem, penicillamine, infliximab,
etanercept, rifampin, quinidine, captopril, beta blockers, anticonvulsants, sulfa, and amiodarone.
Most patients present with arthralgias or arthritis, and about one
half of the patients have serositis. Organ involvement is uncommon
in drug-induced lupus. Serologically, 95% of patients are antihistone
positive, and the Sm and dsDNA are rarely positive. In comparison,
in SLE, most patients are dsDNA positive and 80% are antihistone
positive.55
Diagnosis should be suspected with acute lupus-like clinical
signs and symptoms not involving a major organ and antihistone antibodies without dsDNA antibodies in the setting of an
offending drug. Besides stopping the implicated medication, other

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Psychiatric manifestations of SLE can be either primary and organic

(psychosis, cognitive dysfunction, dementia) or secondary and functional (depression, anxiety, mania, personality disorders). The distinction should be based on psychological testing and on diagnostic
studies such as CT, MRI, electroencephalography, evoked potential
studies, cerebrospinal fluid studies, and single-photon emission CT
(SPECT).52
Psychosis occurs in about 5% of SLE patients either from the
lupus itself or from steroids and is a diagnosis of exclusion. Besides
antipsychotic medications and a strong social support system, high
doses of intravenous steroids have been used for a few weeks in
divided doses. Cytoxan or azathioprine can also be tried if there has
been no improvement with steroids in a couple of weeks.
Cognitive disorders are common and occur in 20% to 80% of
patients. Treatment is based on the cause (drug or disease) and
should also involve cognitive retraining. Dementia is severe cognitive
dysfunction from multiple small ischemic strokes that may be worsened by high doses of steroids; therefore social support and antidepressants are key.53

Neurologic manifestations can be primary (from SLE) or secondary

(due to disease complications and treatment). They can then be
either organic or functional (psychosis).
Seizures occur in one third of the cases and portend a poor overall
prognosis.44 They could be generalized or partial and simple or
complex and can be acute or from chronic scarring. For seizures,
treatment data are scarce, and appropriate antiseizure medications
are used along with a short course of steroids if there is an SLE flare.
CNS vasculitis tends to manifest with fevers, headaches, cognitive
deficits, and confusion in the setting of serologic and radiologic
markers of a lupus flare and can rapidly progress to seizures, loss of
consciousness, and psychosis. Evaluation requires a brain MRI, magnetic resonance angiogram (MRA), and a spinal tap. Treatment is
intravenous pulse steroids followed by oral steroids and cyclophosphamide.
Headaches in lupus are very common, but they have been
reported to have no causal relation, no association with disease severity, and no particular mechanisms and require the regular headache
evaluation, unless there are sudden headaches in a person who was
previously free of headache and who has neurologic and psychiatric
changes.45 SLE headaches are managed as usual headaches unless
there is a definite lupus flare.
Stroke can occur in 19% of patients either from a lupus flare or
from secondary antiphospholipid antibody syndrome.46 Treatment
for stroke is empirical and is tailored to each patient based on the
presentation. General principles of aggressive primary and secondary
stroke prevention also apply in a lupus patient. If a stroke is from
high antiphospholipid antibody (APLA) titers, chronic anticoagulation is recommended if there is no concomitant danger of intracranial hemorrhage. If this is catastrophic APLA syndrome,
plasmapheresis, pulse steroids, and cytoxan are also considered. If
the stroke is from a lupus flare (i.e., is not thrombotic), steroids with
or without cytoxan traditionally have been used.47
Neuropathies can be peripheral, autonomic, or cranial.48 Wrist
drops and foot drops occasionally result from peripheral nerve vasculitis. Besides an electromyogram (EMG), a nerve biopsy could also
be obtained. For EMG-positive peripheral neuropathy, initial treatment is typically higher doses of prednisone, especially in patients
with sensorimotor loss, along with neurontin or tricyclic antidepressants. Steroid-sparing agents such as imuran may be used thereafter.
If the EMG is negative, neurontin or a tricyclic antidepressant should
suffice. With cranial neuropathies, the mainstay of treatment is
higher doses of prednisone.
Movement disorders (chorea and ataxia) tend to be self-limited
without treatment.
Transverse myelitis is coincident with a lupus flare and is a rheumatologic emergency. This manifests with a sudden onset of lower
extremity weakness or sensory loss plus loss of rectal and urinary
bladder sphincter control, usually with clinical symptoms of a lupus
flare.49 Transverse myelitis needs to be aggressively treated with pulse
steroids followed by 1 mg/kg oral prednisone, cytoxan, and, sometimes, plasmapheresis.50
Ophthalmic involvement can occur as a rash on the eyelids,
keratoconjuctivitis, retinal vasculitis, retrobulbar optic neuritis, or
retinal vein or artery occlusions.51 Eye involvement can result from
SLE or concomitant APLA. Ophthalmic treatment options are prednisone, plaquenil, and occasionally cytoxan for optic neuritis that
does not respond to prednisone. If there is retinal artery or vein
involvement from APLA, anticoagulation should be considered.
Meningitis in SLE is rare and has a CSF picture of aseptic
meningitis.

Psychiatric Manifestations

S E C T I O N 13

Neurologic Manifestations

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S E C T I O N 13

R H E U M AT O L O G Y A N D I M M U N O L O G Y

treatment options are NSAIDs, antimalarials, and sometimes steroids and cytotoxic agents for drug-induced vasculitis or serositis.
The disease tends to resolve within 6 months of discontinuing
the drug.

Antiphospholipid Antibody Syndrome

APLA syndrome can be primary (idiopathic) or secondary (e.g., from
SLE, infection, drugs). It causes arterial and venous thromboses
leading to strokes, myocardial infarction, pulmonary embolism, deep
venous thrombosis, fetal loss, anemia, thrombocytopenia, and livedo
reticularislike skin rash. In the clinical setting of lupus, an elevated
partial thromboplastin time (PTT) should raise the suspicion of the
presence of APLAs. Suspicion should be higher in an SLE patient
who suffers a thrombotic event.
Besides a rapid plasma reagin, which gives a false-positive lupus
anticoagulant test result, evaluation should involve a detailed lupus
anticoagulant panel, which should ideally include prothrombin time
(PT), activated PTT, dRVVT/KCT (dilute Russells viper venom
time and kaolin clotting time), mixing study, hex phase screen,
hex phase confirm, platelet neutralization, and circulating anticoagulant. Lupus anticoagulant can be present in healthy subjects and
can be transient in infections, and its presence should be interpreted
in the right clinical and serologic settings. High-titer immunoglobulin (Ig) G/IgM cardiolipin antibodies and 2 glycoprotein have been
associated with higher risk of thrombotic events and should also be
tested.
For a definite diagnosis of APLA, the ACR has criteria. Briefly,
frequent miscarriages and stillbirths or one or more clinical episodes
of arterial or venous thrombosis confirmed by imaging or histology
and the presence of lupus anticoagulant or medium to high titer IgG/
IgM cardiolipin antibody or 2 glycoprotein antibody on at least
two occasions 6 weeks apart is confirmatory for APLA syndrome.
Treatment is mainly anticoagulation and must be tailored to the
clinical setting.56 In a patient with thrombosis and positive ALPA,
heparin initially followed by long-term warfarin therapy is recommended. In a patient with positive ALPA but no thrombotic events,
a trial of prophylactic aspirin 81mg daily (clopidogrel for patients
allergic to aspirin) or aspirin with plaquenil have been tried. In
catastrophic APLA with organ damage, anticoagulation and highdose intravenous steroids for 3 days followed by 1 to 2 mg/kg of
prednisone daily have been used with or without plasmapheresis.
Cyclophosphamide may be added and is most useful in a concomitant acute lupus flare. The traditional belief has been that primary
APLA syndrome might not respond to cytotoxic therapy; however,
cyclophosphamide is sometimes lifesaving in catastrophic APLA syndrome by an unknown mechanism. Intravenous immune globulin
has also been tried in APLA-associated microangiopathies.

DIAGNOSIS
Diagnosis of SLE is made on clinical criteria supported by serologic
data and appropriate imaging studies and biopsies as indicated. The
ACR criteria for SLE are available on the ACR website. Four of 11
criteria are required to make a diagnosis of SLE. Although the criteria are helpful, not all patients fulfill these criteria clinically, and
criteria have to be used with caution in clinical settings.

Tests
A patient referred for incidental positive ANA should have a careful
history and physical examination to look for clinical findings of SLE.
Not all patients with a positive ANA have SLE or a connective tissue
disease. Two percent to 5% of healthy persons carry a low to moderate positive ANA. On the other hand, if there is a clinical suspicion
of SLE, a detailed workup should be initiated with appropriate blood
tests, urine tests, x-rays, and other studies that may be required based
on the presentation.

In an outpatient setting, most rheumatologists order a white

blood cell count (WBC) with differential, comprehensive metabolic
panel (CMP), erythrocyte sedimentation rate (ESR), C-reactive
protein (CRP), ANA panel, Smith, RNP, SSA and SSB, complements
C3 and C4, dsDNA, and a urine analysis. Most rheumatologists also
screen their patients for tuberculosis, hepatitis, thyroid diseases, and
pregnancy, because a positive test affects the choice of immunosuppression and future follow-up. It is also worthwhile to check for
APLAs (lupus anticoagulant, cardiolipin antibodies, and 2 microglobulin) because SLE and APLA commonly coexist and are often
found together in patients with prior thrombotic events or frequent
miscarriages.
If one suspects primary Sjgrens syndrome, rheumatoid factor
(RF), cryoglobulin levels, and 2 microglobulins should be checked.
Primary Sjgrens syndrome patients tend to have a positive ANA,
rheumatoid factor, and SSA or SSB. Occasionally these patients have
sicca symptoms and negative laboratory results, in which case a lip
biopsy with a focus score is required to prove or disprove the diagnosis of primary Sjgrens syndrome. Sjgrens syndrome, however,
can also be secondary to any underlying connective tissue disease,
especially SLE and rheumatoid arthritis.
Other diagnostic tests are ordered as indicated and consist of joint
x-rays and chest x-ray; renal ultrasound; CT scans of the chest,
abdomen, and pelvis; echocardiograms; CT angiograms; electromyography and nerve conduction tests; neuropsychiatric testing; vascular studies; and biopsies of the skin, kidneys, nerves, and lungs.

Diagnosis
In the right clinical setting, leukopenia or lymphopenia, anemia, or
thrombocytopenia with a positive ANA of 1:60 or higher suggests a
diagnosis of SLE. The ANA panel might exhibit antibody patterns
such as dsDNA, RNP, Smith, SSA, SSB, or histones. If it does, other
multisystem diseases should be considered in addition to SLE,
including Sjgrens syndrome, myositis, or drug-induced lupus,
depending on the clinical features and autoantibodies isolated.
Table 1 lists some of the common tests and expected abnormalities, the possible mechanisms, clinical features, autoantibodies, and
suggested specificities.57 This table is not a standardized guideline,
and tests can vary in different clinical settings. The clinical assessment and tests must be combined to make an appropriate diagnosis
of SLE.

Assessing Organ Risk and Activity

If the SLE is active, the ESR and CRP are usually elevated, although
sometimes they are normal. The complements C3 and C4 are usually
low, especially in the setting of organ involvement such as the
kidneys, but they can also be normal. A urine analysis is very important, and one must look for evidence of microscopic blood and
proteinuria. If there is proteinuria, a 24-hour urine protein-tocreatinine ratio should be checked. If the dipstick is positive for
blood, the urine should be manually spun in a centrifuge to look for
dysmorphic red cells, granular casts, hyaline casts, and red blood cell
or mixed casts to rule out renal involvement from SLE. Red cell casts
and mixed casts tend to suggest inflammatory activity in the glomeruli and usually indicate the need for a kidney biopsy and referral
to a nephrologist. If other organs are involved, such as the brain,
lungs, or GI tract, appropriate laboratory, imaging, and biopsy
studies may be required.

Follow-up Data
If immunosuppressive treatment is started with methotrexate, azathioprine, or mycophenolate mofetil, the complete blood count
(CBC), basic metabolic profile, liver function tests, ESR, and CRP
are usually monitored every month for the first 3 months and every
2 months for the next 6 months, and then the intervals are gradually

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Table 1 Diagnostic Tests for Systemic Lupus Erythematosus

Test

Possible Abnormalities

Mechanism

Significance and Use

Disease activity markers for SLE and APLA
Monitor drug side effects

Basic metabolic panel

Elevated BUN/Cr ratio

Immune complex
glomerulonephritis in SLE
Renal artery thrombosis
from APLA

Diagnosis
Follow SLE nephritis
Monitor drug side effects

ESR and CRP

Elevated

Inflammatory markers

Disease activity marker for follow-up if elevated at

diagnosis

Complements (C3, C4)

Low

Immune complex
consumption

Disease activity marker

Low C3 and C4 can also be seen in some primary
complement deficiencies

Urine chemistry

Proteinuria, hematuria, RBCs,

red cell and mixed casts

Glomerulonephritis or
glomerular damage

SLE nephritis and/or nephrotic syndrome

LFTs

Elevated transaminases and/or

alkaline phosphatase
Low protein or albumin

Unknown mechanism or
concomitant NSAID use

Lupus hepatitis, nephrotic syndrome (low albumin), drug

side effects

ANA (IFA + EIA)

Useful as a screening test

+ANA > 1:80 or 1:60 in right
clinical setting are suggestive,
although not diagnostic, of
SLE
Titers > 1:640: look harder for
ANA+ diseases if no obvious
symptoms

ENA panel

Anti-Sm, anti-RNP, antihistone,

anti-SSA/Ro, anti-SSB/La,
antiribosomal P, SCL-70,
and anticentromere
These are not disease activity
markers and are purely
diagnostic

Antibodies to specific
nuclear proteins

Anti-Sm: Highly specific for SLE

Anti-histone: drug-induced lupus (95%) and SLE (80%)
Anti-SSA/SSB: primary Sjgrens syndrome, SCLE, neonatal
lupus and SLE with secondary Sjgrens syndrome
Anti-RNP: SLE (musculoskeletal, Raynauds phenomenon),
MCTD
Antiribosomal P: SLE (psychiatric and CNS)
SCL-70: systemic sclerosis
Anticentromere: CREST syndrome

dsDNA antibody

Positive
Higher titers seem to predict
disease severity at times

Antibodies to the dsDNA

Diagnostic of SLE
May be used as a disease activity marker
Absent in drug-induced lupus
Higher titers in renal involvement

APLAs

Lupus anticoagulant panel,

cardiolipin antibody panel, 2
glycoprotein

Antibodies to membrane
phospholipids

Moderate to high titers of IgG and IgM in primary or

secondary APLA syndrome

ANA-negative lupus is rare (manifests with

photosensitivity, Raynauds syndrome, rash, serositis)
ANA+ can be present in 2%-5% of healthy people and in
other CTDs some of which are RA, JIA, scleroderma,
MCTD, Sjgrens syndrome, dermatomyositis,
polymyositis, Hashimotos thyroiditis, lupoid hepatitis,
and (occasionally) as an epiphenomenon in cancer,
hepatitis, or transient infections ANA is not a disease
activity marker and is mainly diagnostic

APLA, antiphospholipid antibody; BUN, blood urea nitrogen; CBC, complete blood count; CNS, central nervous system; Cr, creatinine; CREST, calcinosis, Raynauds
syndrome, esophageal involvement, sclerodactyly, telangiectasia; CRP, C-reactive protein; CTD, connective tissue disease; dsDNA, double-stranded DNA; EIA,
enzyme immunoassay; ENA, extractable nuclear antigens; ESR, erythrocyte sedimentation rate; IFA, immunofluorescent antibody; Ig, immunoglobulin; JIA, juvenile
idiopathic arthritis; LFTs, liver function tests; MCTD, mixed connective tissue disease; NSAID, nonsteroidal anti-inflammatory drug; RA, rheumatoid arthritis; RBC, red
blood cell count; RNP, ribonuclear protein; SCLE, subacute cutaneous lupus erythematosus; SLE, systemic lupus erythematosus; SS, Sjgrens syndrome.

increased if the results are acceptable. The frequency of blood tests

depends on the choice of immunosuppressive medications. Cyclophosphamide requires more frequent monitoring than the other
cytotoxic agents and should be done by a rheumatologist on a regular
basis. Use of hydroxychloroquine requires only annual eye examinations and is usually used in mild SLE with mucocutaneous, skin,
joint, or serosal symptoms without organ involvement.
The dsDNA, C3, C4, ESR, CRP, CBC, basic metabolic profile,
liver function tests, and urine sediment can all be used as markers of
disease activity. When there is more systemic involvement, such as
the lungs and brain, appropriate imaging studies should also be followed periodically.

TREATMENT
Treatment options include steroids, hydroxychloroquine, dapsone,
azathioprine, methotrexate, mycophenolate mofetil, cyclophosphamide, and rituximab. Two studies of lupus treatment of randomized
controlled trials (RCTs) were recently published. The EXPLORER
(Efficacy and Safety of Rituximab in Patients with SLE) was a phase
II/III randomized, double-blind, placebo-controlled multicenter
trial evaluated treatment with rituximab in patients with active SLE
but excluded patients with active nephritis, or who were being treated
with high-dose prednisone or cytoxan. Preliminary results concluded
that rituximab was not superior to rituximab in these patients. The

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R H E U M AT O L O G Y A N D I M M U N O L O G Y

Autoantibodies to RBCs
(Coombs), lymphocytes,
platelets

Anemia, thrombocytopenia,
leukopenia, lymphopenia,
occasional neutropenia

S E C T I O N 13

CBC plus differential

S E C T I O N 13

R H E U M AT O L O G Y A N D I M M U N O L O G Y

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Systemic Lupus Erythematosus

LUNAR Study (Efficacy and Safety of Rituximab in patients with

ISN/PRS Class II or III lupus nephritis was a phase III randomized,
double-blind, placebo-controlled trial that compared the efficacy
and safety of rituximab plus mycophenylate with placebo plus mycophenylate in SLE patients with proliferative nephritis. Preliminary
results showed that rituximab plus mycophenylate was not superior
to mycophenylate. Treatments have been discussed briefly with each
section separately. Because SLE has a wide spectrum of symptoms
and organ involvement, treatment strategies must be individualized
for each patient, the organ system involved, and the severity of
involvement. Immunosuppressive agents should be used only after
infection and malignancy have been ruled out. In patients undergoing immunosuppressive treatment, physicians must continue to be
vigilant for infections, both common and opportunistic, and for
malignancies. Care of patients with SLE involves ongoing assessment
of the patients lupus activity and other comorbid conditions.
Osteoporosis prevention and treatment (especially in patients
taking steroids), lipid and blood pressure control, antibiotic prophylaxis, and vigilant ongoing age-appropriate malignancy screenings
are all treatment measures that are essential for the care of patients
with SLE.
Standardized measures of disease activity such as SLICC (Systemic Lupus International Collaborating Clinics), BILAG (British
Isles Lupus Assessment Group), and SLE activity scales are usually
used in research settings. The SLICC/ACR damage index for SLE
encompasses net damage from disease, treatment, or other events. A
full history, physical examination, and serologic data such as complements, dsDNA, inflammatory markers, and a urine analysis can be
used as markers of disease activity.

OUTCOME AND PROGNOSIS

Even with better survival rates, the mortality rate from SLE is still
three times higher than the general population. Prognosis is worse
in African American patients, in patients with early-onset disease,
and in patients with renal, cardiopulmonary, and CNS involvement.
Treatment of SLE with immunosuppressive drugs and cytotoxic
agents can result in significant morbidity and mortality from concomitant infections. However, the prognosis for SLE patients in the
United States has improved dramatically since the 1950s due to
improved diagnostic methods, vigilant follow-up, and newer treatment options. Ongoing research and clinical progress will help
improve prognosis and the future quality of life of patients with SLE.
Summary
SLE is a prototypic autoimmune disease that can manifest
with symptoms involving multiple organ systems in all ages
and both sexes, but most initially presenting patients are
women of childbearing age.
l The diagnosis of SLE is based on clinical features and the
presence of autoantibodies. High-titer IgG antibodies to
dsDNA and antibodies to the Smith antigen are both
specific for SLE.
l

ANAs are positive in more than 95% of patients with SLE,

so repeated negative tests make the diagnosis unlikely.
Positive ANAs, especially in low titers, can be seen in up to
30% of healthy persons.
l Lupus manifestations of nephritis, cardiovascular disease,
neurologic disease, pulmonary disease and hematologic
syndromes can require urgent intervention with
immunosuppressive therapies.
l Patients with SLE are at higher risk for some malignancies.
l Patients with SLE are at higher risk of cardiovascular
disease and stroke, and the excess risk is not explained by
traditional risk factors.
l When patients with SLE taking immunosuppressive therapy
present with additional symptoms that could result from
flares of their disease, they must be evaluated to rule out
infection before increasing their immunosuppression.
l

Suggested Readings
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Calvo-Alen J, Toloza SM, Fernandez M, et al: Systemic lupus erythematosus in a multiethnic US cohort (LUMINA). XXV. Smoking, older age, disease activity, lupus
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Hanly JG: ACR classification criteria for systemic lupus erythematosus: Limitations and
revisions to neuropsychiatric variables. Lupus 2004;13(11):861-864.
Jennekens FG, Kater L: The central nervous system in systemic lupus erythematosus.
Part 1. Clinical syndromes: A literature investigation. Rheumatology (Oxford)
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Joseph G, Lammie, GA, Scolding, NJ: CNS lupus: A study of 41 patients. Neurology
2007;69:644-654.
Lockshin MD, Erkan D: Treatment of the antiphospholipid syndrome. N Engl J Med
2003;349:1177-1179.
Maksimowicz-McKinnon K, Magder LS, Petri M: Predictors of carotid atherosclerosis
in systemic lupus erythematosus. J Rheumatol 2006;33(12):2458-2463.
Oelke K, Richardson B: Pathogenesis of lupus. Arthritis Rheum 2002;47(3):343-345.
Peponis V, Kyttaris VC, Tyradellis C, et al: Ocular manifestations of systemic lupus
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References
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