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Systemic Lupus Erythematosus


(SLE)
Updated: Nov 14, 2017
Author: Christie M Bartels, MD, MS; Chief Editor: Herbert S Diamond, MD

Overview

Practice Essentials
Systemic lupus erythematosus (SLE) is a chronic inflammatory disease that has protean manifestations and follows a
relapsing and remitting course. More than 90% of cases of SLE occur in women, frequently starting at childbearing age. See
the image below.

Photosensitive systemic lupus erythematosus (SLE) rashes typically occur on the face or extremities, which are sun-
exposed regions. Although the interphalangeal spaces are affected, the metacarpophalangeal (MCP) and proximal
interphalangeal (PIP) and distal interphalangeal (DIP) joints are spared. Photo courtesy of Dr. Erik Stratman, Marshfield
Clinic.

See Cutaneous Clues to Accurately Diagnosing Rheumatologic Disease, a Critical Images slideshow, to help recognize
cutaneous manifestations of rheumatologic diseases. Also, see the Autoimmune Disorders: Making Sense of Nonspecific
Symptoms slideshow to help identify several diseases that can cause a variety of nonspecific symptoms.

Signs and symptoms

SLE is a chronic autoimmune disease that can affect almost any organ system; thus, its presentation and course are highly
variable, ranging from indolent to fulminant.

In childhood-onset SLE, there are several clinical symptoms more commonly found than in adults, including malar rash,
ulcers/mucocutaneous involvement, renal involvement, proteinuria, urinary cellular casts, seizures, thrombocytopenia,
hemolytic anemia, fever, and lymphadenopathy.[1]

In adults, Raynaud pleuritis and sicca are twice as common as in children and adolescents.[1]
The classic presentation of a triad of fever, joint pain, and rash in a woman of childbearing age should prompt investigation
into the diagnosis of SLE.[2, 3]

Patients may present with any of the following manifestations[4] :

Constitutional (eg, fatigue, fever, arthralgia, weight changes)

Musculoskeletal (eg, arthralgia, arthropathy, myalgia, frank arthritis, avascular necrosis)

Dermatologic (eg, malar rash, photosensitivity, discoid lupus)

Renal (eg, acute or chronic renal failure, acute nephritic disease)

Neuropsychiatric (eg, seizure, psychosis)

Pulmonary (eg, pleurisy, pleural effusion, pneumonitis, pulmonary hypertension, interstitial lung disease)

Gastrointestinal (eg, nausea, dyspepsia, abdominal pain)

Cardiac (eg, pericarditis, myocarditis)

Hematologic (eg, cytopenias such as leukopenia, lymphopenia, anemia, or thrombocytopenia)

In patients with suggestive clinical findings, a family history of autoimmune disease should raise further suspicion of SLE.

See Clinical Presentation for more detail.

Diagnosis

The diagnosis of SLE is based on a combination of clinical findings and laboratory evidence. Familiarity with the diagnostic
criteria helps clinicians to recognize SLE and to subclassify this complex disease based on the pattern of target-organ
manifestations.

The presence of 4 of the 11 American College of Rheumatology (ACR) criteria yields a sensitivity of 85% and a specificity of
95% for SLE.[5, 6]

When the Systemic Lupus International Collaborating Clinics (SLICC) group revised and validated the ACR SLE
classification criteria in 2012, they classified a person as having SLE in the presence of biopsy-proven lupus nephritis with
ANA or anti-dsDNA antibodies or if 4 of the diagnostic criteria, including at least 1 clinical and 1 immunologic criterion, have
been satisfied.[7]

ACR mnemonic of SLE diagnostic criteria


The following are the ACR diagnostic criteria in SLE, presented in the "SOAP BRAIN MD" mnemonic:

Serositis

Oral ulcers

Arthritis

Photosensitivity

Blood disorders

Renal involvement

Antinuclear antibodies

Immunologic phenomena (eg, dsDNA; anti-Smith [Sm] antibodies)

Neurologic disorder

Malar rash

Discoid rash

Testing

The following are useful standard laboratory studies when SLE is suspected:

CBC with differential


Serum creatinine

Urinalysis with microscopy

Other laboratory tests that may be used in the diagnosis of SLE are as follows:

ESR or CRP level

Complement levels

Liver function tests

Creatine kinase assay

Spot protein/spot creatinine ratio

Autoantibody tests

Imaging studies

The following imaging studies may be used to evaluate patients with suspected SLE:

Joint radiography

Chest radiography and chest CT scanning

Echocardiography

Brain MRI/MRA

Cardiac MRI

Procedures

Procedures that may be performed in patients with suspected SLE include the following:

Arthrocentesis

Lumbar puncture

Renal biopsy

See Workup for more detail.

Management

Management of SLE often depends on the individual patient’s disease severity and disease manifestations,[8] although
hydroxychloroquine has a central role for long-term treatment in all SLE patients.

Pharmacotherapy

Medications used to treat SLE manifestations include the following:

Antimalarials (eg, hydroxychloroquine)

Corticosteroids (eg, methylprednisolone, prednisone), short-term use recommended

Nonbiologic DMARDS: Cyclophosphamide, methotrexate, azathioprine, mycophenolate, cyclosporine

Nonsteroidal anti-inflammatory drugs (NSAIDS; eg, ibuprofen, naproxen, diclofenac)

Biologic DMARDs (disease-modifying antirheumatic drugs): Belimumab, rituximab, and/or IV immune globulin

See Treatment and Medication for more detail.

Background
Systemic lupus erythematosus (SLE) is a chronic inflammatory disease that has protean manifestations and follows a
relapsing and remitting course. It is characterized by an autoantibody response to nuclear and cytoplasmic antigens. SLE
can affect any organ system, but it mainly involves the skin, joints, kidneys, blood cells, and nervous system (see
Presentation).
The diagnosis of SLE must be based on the proper constellation of clinical findings (see the image below) and laboratory
evidence. The American College of Rheumatology (ACR) criteria, proposed in 1982 and revised in 1997, summarize
features that may aid in the diagnosis. (See Workup.) Management of this condition depends on the disease severity and
organ involvement. Periodic follow-up and laboratory testing are imperative to detect signs and symptoms of new organ-
system involvement and to monitor the response or adverse reactions to therapies. (See

Treatment.)

The classic malar rash, also known as a butterfly rash, with distribution over the cheeks and nasal bridge. Note that the
fixed erythema, sometimes with mild induration as seen here, characteristically spares the nasolabial folds.

See also the following Medscape articles:

Pediatric Systemic Lupus Erythematosus


Systemic Lupus Erythematosus and Pregnancy
Bullous Systemic Lupus Erythematosus (BSLE)

Pathophysiology
SLE is an autoimmune disorder characterized by multisystem inflammation with the generation of autoantibodies. Although
the specific cause of SLE is unknown, multiple factors are associated with the development of the disease, including
genetic, epigenetic, ethnic, immunoregulatory, hormonal, and environmental factors.[9, 10, 11, 12] Many immune
disturbances, both innate and acquired, occur in SLE (see the image below).

In systemic lupus erythematosus (SLE), many genetic-susceptibility factors, environmental triggers, antigen-antibody (Ab)
responses, B-cell and T-cell interactions, and immune clearance processes interact to generate and perpetuate
autoimmunity. HLA = human leukocyte antigen; UV = ultraviolet light.

Potential mechanisms
It is important to note that antibodies may be present for many years before the onset of the first symptoms of SLE.[13] One
longstanding proposed mechanism for the development of autoantibodies involves a defect in apoptosis that causes
increased cell death and a disturbance in immune tolerance.[14, 15, 10, 16] The redistribution of cellular antigens during
necrosis/apoptosis leads to a cell-surface display of plasma and nuclear antigens in the form of nucleosomes.
Subsequently, dysregulated (intolerant) lymphocytes begin targeting normally protected intracellular antigens. The defective
clearance of the apoptotic cell debris allows for the persistence of antigen and immune complex production.[17]

T cells have long been thought to play a central role in SLE pathogenesis, and T cells from patients with lupus show defects
in both signaling and effector function.[18, 19] These T cells secrete less interleukin (IL)-2, and one defect in signaling
seems to be linked to an increase in calcium influx, possibly due to changes in the CD3 signaling subunits. The following
seem to be adversely affected in T cells from patients with SLE: effector activity such as CD8 cytotoxicity; T-regulatory, B-
cell help; migration; and adhesion. However, the method by which each of these deficits contributes to the exact clinical
syndrome seen in an individual patient is still unknown. These T-cell abnormalities are currently being explored as targets
for therapy, as seen with the recent approval of belimumab, which targets the B-lymphocyte stimulator (BLys) signaling
pathway.[18, 19]

Many clinical manifestations of SLE are mediated by circulating immune complexes that form with antigens in various
tissues or the direct effects of antibodies to cell surface components. Immune complexes form in the microvasculature,
leading to complement activation and inflammation. Moreover, antibody-antigen complexes deposit on the basement
membranes of skin and kidneys. In active SLE, this process has been confirmed by demonstration of complexes of nuclear
antigens such as DNA, immunoglobulins, and complement proteins at these sites.

Autoantibodies have been found to be biomarkers for future neuropsychiatric events in SLE. A prospective study (=10
years) of 1047 SLE patients demonstrated that individuals who had evidence of lupus anticoagulant (LA) had an increased
future risk of intracranial thrombosis and that those with anti-ribosomal P antibodies had an increased future risk of lupus
psychosis.[20]

Serum antinuclear antibodies (ANAs) are found in nearly all individuals with active SLE. Antibodies to native double-
stranded DNA (dsDNA) are relatively specific for the diagnosis of SLE. Whether polyclonal B-cell activation or a response to
specific antigens exists is unclear, but much of the pathology involves B cells, T cells, and dendritic cells. Cytotoxic T cells
and suppressor T cells (which would normally down-regulate immune responses) are decreased. The generation of
polyclonal T-cell cytolytic activity is impaired. Helper (CD4+) T cells are increased. A lack of immune tolerance is observed
in animal lupus models. Reports pointing to important roles of interferon-alpha, transcription factors, and signaling variations
also point to a central role for neutrophils.[21]

Genetics

There is a clear genetic component in SLE, with a sibling risk ratio 8-fold to 29-fold higher than that in the general population
and a 10-fold increase in disease concordance in identical twins. In addition, there is a 24-56% concordance rate in
monozygotic twins, compared with a 2-5% risk in dizygotic twins.[22]

Although some single genes have been implicated to play a causative role in SLE, current knowledge points toward a large
number of genes being involved in a multifactorial-type inheritance pattern in most patients.[23, 24] Genome-wide
association studies have identified more than 60 risk loci for SLE susceptibility across populations, with most of the genetic
risk shared across borders and ethnicities.[25]

Many of the loci with a strong association with SLE are involved in the immune and related biologic systems.[22] Genes
previously associated with other autoimmune diseases have been associated with SLE (eg, PTPN22 and diabetes; STAT4
and rheumatoid arthritis).

Genetic studies point to disruptions in lymphocyte signaling, interferon response, clearance of complement and immune
complexes, apoptosis, and DNA methylation.[26] Several genes associated with T-cell function and signaling have been
associated with SLE, including PTPN22, TNFSF4, PDCD1, IL10, BCL6, IL16, TYK2, PRL, STAT4, and RASGRP3, as have
immune-complex processing and innate immunity genes, including several complement genes (eg, C2, C4A, and C4B).[27]

A meta-analysis of the association of interferon regulatory factor 5 (IRF5) with SLE found that a specific T allele, IRF5
rs2004640, is significantly associated with SLE in populations of European, Asian, and Latin American origins, whereas the
A allele IRF5 rs10954213 is associated with SLE in patients of European origin but not in those of Asian origin.[28] Overall,
the IRF5 gene polymorphism was found to be associated with SLE in multiple ethnic populations. The results also offer
insights into the epigenetics of SLE: Hypomethylation (a form of epigenetic modification) of genes involved in osmotic lysis,
apoptosis, inflammation, and cytokine pathways, among other immunologic functions, have been associated with this
disease.[28]

For further discussion, see Genetics of Systemic Lupus Erythematosus

Etiology
Although the specific cause of SLE is unknown, multiple genetic predispositions and gene-environment interactions have
been identified (see the chart in the image below). This complex situation perhaps explains the variable clinical
manifestations in persons with SLE.

In systemic lupus erythematosus (SLE), many genetic-susceptibility factors, environmental triggers, antigen-antibody (Ab)
responses, B-cell and T-cell interactions, and immune clearance processes interact to generate and perpetuate
autoimmunity. HLA = human leukocyte antigen; UV = ultraviolet light.

SLE has a modest recurrence rate in families: 8% of affected patients have at least one first-degree family member
(parents, siblings, and children) with SLE; this is in contrast to 0.08% of the general population.[29] In addition, SLE occurs
in both twins in 24% of identical twins and 2% of nonidentical twins, which may be due to a combination of genetic and
environmental factors.[29]

Some studies have synthesized what is known about the mechanisms of SLE disease and genetic associations.[10, 26, 30]
At least 35 genes are known to increase the risk of SLE.[26] A genetic predisposition is supported by 40% concordance in
monozygotic twins; if a mother has SLE, her daughter's risk of developing the disease has been estimated to be 1:40, and
her son's risk, 1:250.[26, 30]

A genome-wide study in a northern European population replicated the association of SLE with susceptibility genes related
to B-cell receptor pathway signaling, as well as confirmed the association of SLE with genes at the interferon regulatory
factor 5 (IRF5)-TNPO3 locus.[31] The investigators also confirmed other loci associations with SLE (TNFAIP3, FAM167A-
BLK, BANK1 and KIAA1542); however, it was determined that these loci had a lower significance level and a lower
contribution to individual risk for SLE.[31]

Studies of human leukocyte antigens (HLAs) reveal that HLA-A1, HLA-B8, and HLA-DR3 are more common in persons with
SLE than in the general population. The presence of the null complement alleles and congenital deficiencies of complement
(especially C4, C2, and other early components) are also associated with an increased risk of SLE.

Numerous studies have investigated the role of infectious etiologies that may also perpetuate autoimmunity.[32] Patients
with SLE have higher titers of antibodies to Epstein-Barr virus (EBV), have increased circulating EBV viral loads, and make
antibodies to retroviruses, including antibodies to protein regions homologous to nuclear antigens. In patients with SLE and
EBV infection, the B cells are not primarily defective; rather, the SLE/EBV phenomenon is due to a T-cell abnormality, which
causes failure in normal immunoregulation of the B-cell response.[33] Viruses may stimulate specific cells in the immune
network. Chronic infections may induce anti-DNA antibodies or even lupuslike symptoms, and acute lupus flares often follow
bacterial infections.

Environmental and exposure-related causes of SLE are less clear. Possible early-life risk factors include the following[34] :

Low birthweight (<2,500 g)


Preterm birth (≥1 month early)
Childhood exposure to agricultural pesticides

Other potential factors include the following:

Silica dust and cigarette smoking may increase the risk of developing SLE

Administration of estrogen to postmenopausal women appears to increase the risk of developing SLE.

Photosensitivity is clearly a precipitant of skin disease

Ultraviolet light stimulates keratinocytes, which leads not only to overexpression of nuclear ribonucleoproteins
(snRNPs) on their cell surfaces but also to the secretion of cytokines that simulate increased autoantibody
production.[35]
Breastfeeding is associated with a decreased risk of developing SLE

Pregnancy can be a time when lupus initially presents or flares, although more recent data suggests that pregnancy
outcomes are favorable and flares are infrequent among patients with inactive or stable mild-moderated SLE.[36]

Vitamin D is involved in both in both innate and acquired immunity, and vitamin D deficiency has been implicated in
autoimmunity and the development of rheumatic diseases, including SLE.[37, 38] Young et al studied 436 individuals who
reported having a relative with SLE but who did not have SLE themselves, and found that the combination of vitamin D
deficiency and carriage of specific single-nucleotide polymorphisms was associated with significantly increased risk of
transitioning to SLE.[39] Hu et al reported that in an Asian population, carriage of certain polymorphisms in the vitamin D
receptor gene BsmI (Bb + BB genotype and B allele) can significantly increase risk for developing SLE.[40]

Epidemiology
United States statistics

Estimates of the annual incidence of SLE from the 1970s to 2000s have ranged from approximately 1 to 10 per 100,000
population, while the prevalence of SLE has been estimated to range from approximately 5.8 to 130 per 100,000 population.
[41]

The Lupus Foundation of America estimates prevalence to be at least 1.5 million cases,[42] which likely reflects inclusion of
milder forms of the disease. A 2008 report from the National Arthritis Data Working Group estimated a prevalence of
161,000 cases of definite SLE and 322,000 cases of definite or probable SLE.[43]

The frequency of SLE varies by race and ethnicity, with higher rates reported in blacks and Hispanics. A study in the
predominantly white population of Olmsted County, Minnesota found an age-adjusted prevalence of 30.5 per 100,000
population.[41] In a study of a racially diverse population in Michigan, the prevalence of SLE was 2.3-fold higher in blacks
than in whites; in that study, the age-adjusted prevalence of lupus in blacks was 105.8 or 103 per 100,000 population,
depending on whether the ACR or a rheumatologiist's definition of SLE was used.[44]

Registries have been established in San Francisco and New York City to provide annual prevalence estimates for Hispanics
and Asians,[45] but a 2001 study found a prevalence of 100 per 100,000 Hispanics in Nogales, Arizona.[46]

In the Michigan study, the prevalence of SLE was 10-fold higher in females than in males and was over twice as high in
black females as in white females, reaching 1 in 537 among black females.[44] SLE is also more frequent in Asian women
than in white women.[47]

International statistics

Worldwide, the prevalence of SLE varies. The highest rates of prevalence have been reported in Italy, Spain, Martinique,
and the United Kingdom Afro-Caribbean population.[48] Although the prevalence of SLE is high in black persons in the
United Kingdom, the disease is rarely reported in blacks in Africa, suggesting that there may be an environmental trigger, as
well as a genetic basis, for disease in the UK population.[49]

Race-, sex-, and age-related demographics

Worldwide, the prevalence of SLE appears to vary by race. However, there are different prevalence rates for people of the
same race in different areas of the world. The contrast between low reported rates of SLE in black women in Africa and high
rates in black women in the United Kingdom suggests that there are environmental influences.[49] In general, black women
have a higher rate of SLE than women of any other race, followed by Asian women and then white women.[48]

In the United States, black women are two to four times more likely to have SLE than white women.[44, 48] A review of SLE
across Asia-Pacific countries revealed considerable variation in prevalence and survival rates.[50] For example, overall
prevalence rates ranged from 4.3 to 45.3 per 100,000, and the overall incidence ranged from 0.9 to 3.1 per 100,000 per
year. Moreover, Asians with SLE had higher rates of renal involvement than whites did, and cardiovascular involvement was
a leading cause of death in Asians.[50]

Female-to-male ratio

More than 90% of cases of SLE occur in women, frequently starting at childbearing age.[32, 51] The use of exogenous
hormones has been associated with lupus onset and flares, suggesting a role for hormonal factors in the pathogenesis of
the disease.[52] The risk of SLE development in men is similar to that in prepubertal or postmenopausal women.
Interestingly, in men, SLE is more common in those with Klinefelter syndrome (ie, genotype XXY), further supporting a
hormonal hypothesis. In fact, a study by Dillon et al found that men with Klinefelter syndrome had a more severe course of
SLE than women but a less severe course than other men.[53]
The female-to-male ratio peaks at 11:1 during the childbearing years.[54] A correlation between age and incidence of SLE
mirrors peak years of female sex hormone production. Onset of SLE is usually after puberty, typically in the 20s and 30s,
with 20% of all cases diagnosed during the first 2 decades of life.[55]

A review of the worldwide literature (predominantly North America, Europe, and Asia) found that the incidence of pediatric-
onset SLE ranged from 0.36 to 2.5 per 100,000 per year and the prevalence ranged from 1.89 to 25.7 per 100,000.[56]

The prevalence of SLE is highest in women aged 14 to 64 years. SLE does not have an age predilection in males, although
it should be noted that in older adults, the female-to-male ratio falls.[57] This effect is likely due to loss of the estrogen effect
in older women.

Prognosis
Systemic lupus erythematosus (SLE) carries a highly variable prognosis for individual patients. The natural history of SLE
ranges from relatively benign disease to rapidly progressive and even fatal disease. SLE often waxes and wanes in affected
individuals throughout life, and features of the disease vary greatly between individuals.

The disease course is milder and survival rate higher in persons with isolated skin and musculoskeletal involvement than in
those with renal disease[58] and CNS disease.[59] A consortium report of 298 SLE patients followed for 5.5 years noted
falls in SLE Disease Activity Index 2000 (SLEDAI-2K) scores after the first year of clinical follow-up and gradual increases in
cumulative mean Systemic Lupus International Collaborating Clinics (SLICC) damage index scores.[60]

It is important to distinguish between the disease activity and the damage index (irreversible organ dysfunction). Although
the most effective instrument to measure SLE disease activity is still open to debate, there are several validated measures,
including the Systemic Lupus Activity Measure (SLAM), SLEDAI, Lupus Activity Index (LAI), European Consensus Lupus
Activity Measurement (ECLAM), and British Isles Lupus Activity Group (BILAG) Index.

Prognostic factors from the 2008 European League Against Rheumatism (EULAR) recommendations included the
following[61] :

Clinical findings: Skin lesions, arthritis, serositis, neurologic manifestations such as seizures and psychosis, and
renal involvement

Diagnostic study results: Anemia, thrombocytopenia, leukopenia, increased serum creatinine levels

Immunologic test results: Serum C3 and C4 concentration (which may be low), as well as the presence of anti–
double-stranded DNA (anti-dsDNA), anti-Ro/ Sjögren syndrome A (SSA), anti-La/Sjögren syndrome B (SSB), and
antiphospholipid (aPL), and anti-ribonucleoprotein (anti-RNP)

Mortality

Mortality in patients with SLE has decreased over the past few decades.[62] Prior to 1955, the 5-year survival rate in SLE
was less than 50%; currently, the average 10-year survival rate exceeds 90%,[63, 59] and the 15-year survival rate is
approximately 80%.[64] Previously, mortality was due to the disease itself; currently, mortality is often a result of medication
side effects (eg, fatal infections in individuals receiving potent immunosuppressive medications) or cardiovascular events.

Ten-year survival rates in Asia and Africa are significantly lower than those in the United States, ranging from 60-70%,[65,
66] but this may reflect detection bias of severe cases only.

Decreased mortality rates associated with SLE can be attributed to earlier diagnosis (including milder cases), improvement
in disease-specific treatments, and advances in general medical care. According to the Centers for Disease Control and
Prevention (CDC), however, 35% of SLE-related deaths in the United States occur in patients younger than 45 years,
making this a serious issue despite declining overall mortality rates.[45]

The EULAR task force also identified the following comorbidities as increasing the risk of morbidity and mortality in patients
with SLE[61] :

Infections

Hypertension

Lipid disorders (dyslipidemia), atherosclerosis, and coronary heart disease

Diabetes mellitus

Bone-related conditions: Osteoporosis; avascular bone necrosis

Malignancies such as non-Hodgkin lymphoma, lung cancer, and hepatobiliary cancer


In 1976, Urowitz first reported bimodal mortality in early versus late SLE, noting that SLE-related deaths usually occurred
within the first 5-10 years of symptom onset.[67] Mortality in the first few years of illness is typically from severe SLE disease
(eg, CNS, renal, or cardiovascular involvement) or infection related to immunosuppressive treatment. Infections account for
29% of all deaths in these patients.[68]

Late deaths (after age 35 years) are generally from myocardial infarction or stroke secondary to accelerated
atherosclerosis[62, 69, 63, 70] ; inflammation is central to SLE pathogenesis and plays a major role in the development and
accelerated progression of atherosclerosis. Manzi et al reported that women aged 35-44 years with SLE were 50 times
more likely to develop myocardial ischemia than healthy Framingham study control women.[69] The presence of lupus
nephritis may increase these risks.[71] The presence of traditional and nontraditional risk factors increases the risk of
cardiovascular (CVD) disease in patients with SLE.

In a study by Petri et al that evaluated a large sample of SLE patients, the investigators reported that more than 50% of
these patients had at least 3 classic cardiac risk factors, with the most common ones being a sedentary lifestyle, obesity,
and hypercholesterolemia.[72] In another study, Salmon et al found that nontraditional CVD risk factors in SLE patients
included having higher homocysteine levels, renal impairment, enhanced LDL oxidation, and chronic inflammation.[73]

Causes of accelerated coronary artery disease in persons with SLE are likely multifactorial. They include endothelial
dysfunction, inflammatory mediators, corticosteroid-induced atherogenesis, and dyslipidemia.

The influence of race on prognosis has been widely debated. The LUMINA study group examined SLE in black, white, and
Hispanic patients in the United States (including Puerto Rico) and reported that both disease activity and poverty predicted
higher mortality in racial and ethnic minorities.[74] In the Michigan Lupus Epidemiology and Surveillance program, the
proportion of patients with renal disease was 2.2-fold higher, and that of progression to end-stage renal disease was 3.4-fold
higher, in blacks than in whites.[44]

Patient Education
Stress the importance of adherence to medications and follow-up appointments for detection and control of SLE disease.
Instruct patients with SLE to seek medical care for evaluation of new symptoms, including fever. Advise them regarding their
heightened risks for infection and cardiovascular disease. Educate patients with SLE regarding aggressive lipid and blood
pressure goals to minimize the risk of coronary artery disease.

Instruct patients with SLE to avoid exposure to sunlight and ultraviolet light. Also, encourage them to receive nonlive
vaccines during stable periods of disease, to quit smoking, and to carefully plan pregnancies.

For patient education information, see the Arthritis Center, as well as Lupus (Systemic Lupus Erythematosus ).

See also the American College of Rheumatology’s patient fact sheets for SLE, Systemic Lupus Erythematosus in Children
and Teens, and Antiphospholipid Syndrome.

Presentation

History
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can affect almost any organ system. Its
presentation and course are highly variable, ranging from indolent to fulminant.

In a meta-analysis that reviewed the clinical manifestations of childhood-onset and adult-onset SLE, there were several
statistically significant clinical symptoms more commonly found in childhood-onset SLE, including malar rash,
ulcers/mucocutaneous involvement, renal involvement, proteinuria, urinary cellular casts, seizures, thrombocytopenia,
hemolytic anemia, fever, and lymphadenopathy. Raynaud pleuritis and sicca were twice as common in adults as in children
and adolescents.[1]

The classic presentation of a triad of fever, joint pain, and rash in a woman of childbearing age should prompt investigation
into the diagnosis of SLE.[2, 3] However, patients may present with any of the following types of manifestations[4] :

Constitutional

Musculoskeletal

Dermatologic

Renal
Neuropsychiatric

Pulmonary

Gastrointestinal

Cardiac

Hematologic

In patients with suggestive clinical findings, a family history of autoimmune disease should raise further suspicion of SLE.

Constitutional

Fatigue, fever, arthralgia, and weight changes are the most common symptoms in new cases or recurrent active SLE flares.
Fatigue, the most common constitutional symptom associated with SLE, can be due to active SLE, medications, lifestyle
habits, or concomitant fibromyalgia or affective disorders.

SLE-specific fatigue or fever generally occurs in concert with other clinical markers. Fever may reflect active SLE, infection,
and reactions to medications (ie, drug fever). Always exclude an infectious etiology; patients with SLE are considered
immunocompromised and are therefore at higher risk for developing infections and complications. Most infections are
bacterial in origin, but clinicians should always consider the possibility of atypical and opportunistic infections, particularly
when these individuals are receiving immunomodulating or immunosuppressive therapy. Careful history taking may help
differentiate between the potential causes of fatigue or fever. Note that an acute infectious process may also trigger SLE
and that the two can occur concomitantly.

Weight loss may occur in patients with active SLE. Weight gain may also be due to corticosteroid treatment or active
disease, such as nephrotic syndrome (with anasarca) or myocarditis.

Musculoskeletal

Joint pain is one of the most common reasons for the initial clinical presentation of patients with SLE. Arthralgia, myalgia,
and frank arthritis may involve the small joints of the hands, wrists, and knees (usually symmetrical, polyarticular). In
contrast to rheumatoid arthritis, SLE arthritis or arthralgia may be asymmetrical, with pain that is disproportionate to
swelling.

SLE arthropathy is rarely erosive or deforming. Characteristic hand deformities are swan neck deformities that result from
recurrent synovitis and inflammation of the joint capsule, tendons, and ligaments. These deformities are usually reducible
and nonerosive (resembling Jaccoud arthropathy, which is a nonerosive arthritis following acute rheumatic fever).

Another important consideration is the increased prevalence of avascular necrosis (AVN) in the SLE population relative to
healthy individuals. It may be due to SLE pathogenesis and/or concomitant heavy steroid use.[75] Asymptomatic AVN is
seen in up to 44% of SLE patients in the first year of therapy with high-dose corticosteroids. The most commonly affected
site is the femoral head.[75] Independent risk factors for AVN in patients with SLE include the use of glucocorticosteroid or
cytotoxic agents and the presence of arthritis.[76]

Dermatologic

Cutaneous manifestations of SLE include 3 American College of Rheumatology (ACR) lupus diagnostic criteria: malar rash,
photosensitivity, and discoid lupus.

The first criterion is a malar rash[77] characterized by an erythema over the cheeks and nasal bridge (but sparing the
nasolabial folds, which is in contrast to the rash of dermatomyositis) (see the image below). It lasts from days to weeks and
is occasionally painful or pruritic.
The classic malar rash, also known as a butterfly rash, with distribution over the cheeks and nasal bridge. Note that the
fixed erythema, sometimes with mild induration as seen here, characteristically spares the nasolabial folds.

The second diagnostic feature is photosensitivity, which may be either acute or chronic.[77] The history of photosensitivity
may be elicited from patients by asking if they have had any unusual rash or symptom exacerbation after sun exposure, with
expected duration of approximately 2 days in classic cases.

The third feature is discoid lupus, a chronic lupus rash.[77] Discoid lesions often also develop in sun-exposed areas but are
plaquelike in character, with follicular plugging and scarring. They may be part of systemic lupus or may represent discoid
lupus without organ involvement, which is a separate diagnostic entity. Discoid lesions can develop in up to 25% of patients
with SLE; a small case series suggested that the presence of such lesions may indicate milder disease or less renal
involvement.[78] In another review, it was reported that patients with discoid lesions rarely progressed to systemic SLE
disease; there is a 5% risk of discoid lupus disease developing into the systemic condition.[79]

Subacute cutaneous lupus is a rash seen in up to 10% of SLE cases, but importantly, 50% of patients with this condition will
have it in isolation without systemic lupus.[77] The characteristic lesion appearance is an annular or psoriaform patch with
crusted margins. Lesions often occur on the limbs or torso in sun-exposed areas. Alopecia is an often less specific
cutaneous feature of SLE. It often affects the temporal regions or creates a patchy pattern of hair loss.

Other cutaneous manifestations related to, but not specific to, SLE include the following:

Raynaud phenomenon

Livedo reticularis

Panniculitis (lupus profundus)

Bullous lesions

Vasculitic purpura

Telangiectasias

Urticaria

Renal

The kidney is the most commonly involved visceral organ in SLE. Although only approximately 50% of patients with SLE
develop clinically evident renal disease, biopsy studies demonstrate some degree of renal involvement in most patients.[80]
Therefore, it is important to correctly classify the extent of renal involvement in SLE to improve the correlation between
histologic findings and the prognosis of the renal disease (see Biopsies and Histologic Features under Workup).Glomerular
disease usually develops within the first few years of SLE onset and is often asymptomatic.

Acute or chronic renal failure may cause symptoms related to uremia and fluid overload. Acute nephritic disease may
manifest as hypertension and hematuria. Nephrotic syndrome may cause edema, weight gain, or hyperlipidemia.

For additional information, see the Medscape Reference article Lupus Nephritis.

Neuropsychiatric
The CNS lupus nomenclature has been revised to catalog many manifestations.[81, 82, 83] Because of the difficulty
distinguishing causal SLE associations with some neurologic symptoms, only seizure and psychosis were typically included
in the diagnostic criteria. Seizures related to SLE may be generalized or partial and may precipitate status epilepticus.
Psychosis may manifest as paranoia or hallucinations.

However, the American College of Rheumatology (ACR) created standardized case definitions and diagnostic testing
recommendations for 19 neuropsychiatric syndromes in SLE, including seizures/seizure disorders and psychosis.[84] The
remainder of the neuropsychiatric syndromes are as follows[84] :

Acute confusional state

Acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barre syndrome)

Anxiety disorder

Aseptic meningitis

Autonomic disorder

Cerebrovascular disease

Cognitive dysfunction

Cranial neuropathy

Demyelinating syndrome

Headache

Mononeuropathy (single/multiplex)

Mood disorders

Movement disorder (chorea)

Myasthenia gravis

Myelopathy

Plexopathy

Polyneuropathy

Delirium represents a spectrum of fluctuating altered consciousness characteristic of SLE. Delirium may be caused by CNS
vasculitis, encephalopathy, cerebritis, or the manifestations previously called organic brain syndrome. Aseptic meningitis,
myelopathy, optic neuropathy, or other demyelinating disorders may also require urgent evaluation.

Transverse myelitis with spastic paraparesis and sensory loss at a given level is a rare but severe complication of SLE or
antiphospholipid antibody syndrome. Stroke and transient ischemic attack (TIA) may be related to antiphospholipid antibody
syndrome or SLE vasculitis. Posterior reversible encephalopathy syndrome (PRES) is, as the name implies, a reversible
encephalopathy linked to hypertension that even may be a presenting feature for young SLE patients.[85]

Cognitive disorders may be variably apparent in many patients with SLE. Formal neuropsychiatric testing reveals deficits in
21-67% of patients with SLE. Whether this represents true encephalopathy, neurologic damage, medication effects,
depression, or some other process is unclear. A 2010 multicenter study found that depression was associated with
significantly poorer cognitive function in 111 patients newly diagnosed with SLE.[86]

Migraine headaches may be linked to antiphospholipid syndrome. Headache and mood disorders may be the most
commonly reported neurologic manifestation of SLE, but cause and effect may be difficult to distinguish.

Acute psychiatric manifestations in CNS lupus should be considered as a diagnosis of exclusion in an SLE patient.

For additional information, see the Medscape Reference article Neurologic Manifestations of Systemic Lupus
Erythematosus.

Pulmonary

Pulmonary features of SLE may manifest acutely or indolently, representing a spectrum of SLE complications. SLE may
lead to multiple pulmonary complications, including pleurisy, pleural effusion, pneumonitis, pulmonary hypertension, and
interstitial lung disease. The chronic steroids prescribed to patients also place them at increased risk for atypical infections.

Pleuritis is one of the formal diagnostic criteria for SLE, and it can induce chest pain and a pleural effusion. The pleural
effusion in lupus is exudative, with an elevated lactate dehydrogenase level. Pleurisy with pleuritic chest pain with or without
pleural effusions is the most common feature of acute pulmonary involvement in SLE. Shortness of breath or dyspnea may
be due to many causes. Pulmonary embolism, lupus pneumonitis, chronic lupus interstitial lung disease, pulmonary
hypertension, complement-mediated pulmonary leukoaggregation, alveolar hemorrhage, or infection may be related to lupus
disease.

Most seriously, hemoptysis may herald diffuse alveolar hemorrhage, a rare, acute, life-threatening pulmonary complication
of SLE.

Gastrointestinal

In general, gastrointestinal symptoms secondary to SLE are less common than adverse effects of medication or nonspecific
complaints. Special consideration should be given to infectious causes (bacterial, viral [eg, CMV]), because of
immunosuppression. Nausea and dyspepsia are common symptoms in patients with active SLE and are sometimes difficult
to correlate with objective evidence of gastrointestinal involvement. Peptic ulcer disease is a common complication,
especially in SLE patients treated with nonsteroidal anti-inflammatory agents (NSAIDs) and glucocorticoids.[87]

Occasional abdominal pain in active SLE may be directly related to active lupus, including peritonitis, pancreatitis,
mesenteric vasculitis, and bowel infarction. Jaundice due to autoimmune hepatobiliary disease may also occur.

Cardiac

Heart failure or chest pain must be carefully assessed in patients with SLE. Pericarditis is the most common cardiac feature
of SLE, manifesting as positional chest pain that is often relieved when the patient leans forward. Myocarditis may occur in
SLE with heart failure symptoms. Pulmonary hypertension may present with indolent chest pain or dyspnea.

Coronary vasculitis manifesting as angina or infarction is rarely reported. Libman-Sacks endocarditis is noninfectious but
may manifest as symptoms similar to those of infective endocarditis in patients with SLE or antiphospholipid syndrome.
More commonly, accelerated ischemic coronary artery disease (CAD) is associated with SLE and may present indolently as
atypical anginal equivalents.

Hematologic

A history of multiple cytopenias such as leukopenia, lymphopenia, anemia, or thrombocytopenia may suggest SLE, among
other etiologies, such as medication-related cytopenias. Leukopenia and, more specifically, lymphopenia are common in
SLE; this, coupled with immunosuppression, may predispose persons with SLE to frequent infections.

Anemia is occasionally overlooked in young menstruating women, and a history of lymphopenia may be overlooked.
Thrombocytopenia may be mild or part of a full thrombotic thrombocytopenic purpura (TTP)–like syndrome or
antiphospholipid antibody syndrome. A history of recurrent early miscarriages or a single late pregnancy loss may be clues
to lupus or isolated antiphospholipid antibody syndrome.[88]

Physical Examination
Almost any organ system can be involved in active SLE. The constellation of several physical findings may suggest a
diagnosis of SLE. The American College of Rheumatology (ACR) diagnostic criteria are discussed in Workup. Examination
findings are discussed by system.[4]

Fever is a challenging problem in SLE. It can be a manifestation of active lupus, infection, malignancy, or a drug reaction.
Low-grade fever is observed in patients on immunosuppressive agents, and lymphadenopathy or splenomegaly may be
found.

In patients with fever, infectious causes—both viral and bacterial—need to be ruled out. Lupus patients may be functionally
asplenic and may be at risk for encapsulated bacterial infections such as meningococcemia. Patients with SLE who are on
immunosuppressive therapy are at a higher risk of death due to viral infection (eg, herpes simplex virus [HSV],
cytomegalovirus [CMV], varicella-zoster virus [VZV]) and should be treated accordingly if an infection is suspected.[89] An
infection can mimic a lupus flare, and delays in diagnosis and treatment can increase the risk of mortality.[90]

A postdiagnostic 5-year follow-up study showed that males had a higher prevalence of thromboses, nephropathy, strokes,
gastrointestinal symptoms, and antiphospholipid syndrome and that females were more likely to present with arthralgia, hair
loss, Raynaud syndrome, and photosensitivity.[91] In addition, male patients were more likely to present with tendonitis,
myositis, nephropathy, and respiratory tract infections.

Skin and mucous membrane findings

Malar rash is a fixed erythema that typically spares the nasolabial folds. It is a butterfly-shaped rash that can be flat or raised
over the cheeks and bridge of the nose (see the images below).
The classic malar rash, also known as a butterfly rash, with distribution over the cheeks and nasal bridge. Note that the
fixed erythema, sometimes with mild induration as seen here, characteristically spares the nasolabial folds.

Dermatomyositis. Acute onset of confluent macular erythema in a periorbital and malar distribution (involving the cheeks
and extending over the nasal bridge), with extension to the chin in a female with juvenile dermatomyositis. Note the
perioral sparing. In some patients, there may be more extensive involvement of the face, including the perioral region,
forehead, lateral face, and ears. In contrast to SLE , in dermatomyositis with malar erythema, the nasolabial folds are
often not spared.

Photosensitive rash is often macular or diffusely erythematous in sun-exposed areas of the face, arms, or hands and
generally persists for more than 1 day (see the image below).
Photosensitive systemic lupus erythematosus (SLE) rashes typically occur on the face or extremities, which are sun-
exposed regions. Although the interphalangeal spaces are affected, the metacarpophalangeal (MCP) and proximal
interphalangeal (PIP) and distal interphalangeal (DIP) joints are spared. Photo courtesy of Dr. Erik Stratman, Marshfield
Clinic.

Discoid rash occurs in 20% of patients with SLE and can result in disfiguring scars. The discoid rash can present as
erythematous patches with keratotic scaling over sun-exposed areas of the skin. Follicular plugging may create scarring that
may be well demonstrated in the ears. Systemic manifestations of SLE may be absent (ie, limited discoid lupus).

Lupus should be considered in all patients who experience oral, or less frequently, vaginal ulcers; ulcers classically occur
more than 3 times per year and are painless. Palatal ulcers are most specific for SLE.

Many other cutaneous findings are not explicitly diagnostic features but support impressions of SLE. Alopecia in SLE often
causes hair loss at the temporal regions or creates a patchy pattern. Vascular lesions such as livedo reticularis
(characterized by a lacy, mottled, erythematous skin pattern), periungual erythema (as seen in nailfold capillaroscopy, which
can be performed with an ophthalmoscope to search for dilated capillary nailfold loops), telangiectasias, and Raynaud
phenomenon (blue, white, and red color changes at the distal digital tips) may develop in some patients with SLE or
antiphospholipid antibody syndrome. However, these are nonspecific findings, as they can occur in other connective tissue
disorders with prominent vascular involvement, such as scleroderma and dermatomyositis. Panniculitis, bullous lesions,
vasculitic purpura, and urticaria are other skin lesions that are sometimes seen in SLE.

Musculoskeletal

Arthritis of the proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints of the hands, as well as the wrists, is
the most common musculoskeletal finding in SLE. Tenderness, edema, and effusions accompany a polyarthritis that is
symmetric, nonerosive, and usually nondeforming. Jaccoud arthropathy is the term used to describe the nonerosive hand
deformities due to chronic arthritis and tendonitis that develop in 10% of patients with SLE.

Myositis may manifest as weakness in SLE but is more commonly related to overlap syndromes or corticosteroid-induced
myopathy. Fibromyalgia, distinguished as myofascial tenderness without weakness, is commonly concomitant with SLE,
causing generalized widespread pain, arthralgia, and myalgia.

With focal pain in areas such as the hips, knees, and shoulders, consider avascular necrosis in patients who are taking
glucocorticoids. Consider septic arthritis when one joint is inflamed out of proportion to all other joints or if fever is present.

Renal

Hypertension or hematuria may signal nephritic SLE. Edema of periorbital or peripheral regions, anasarca, and morning
presacral edema upon arising from bed are common physical findings related to nephrotic syndrome or volume overload
with renal failure. Specific signs and symptoms of renal disease may not be apparent until advanced nephrotic syndrome or
renal failure is present; therefore, it is important to obtain a urine analysis, protein estimate, serum BUN, and creatinine level
on a regular basis.

Neuropsychiatric

About 28-40% of neuropsychiatric SLE findings arise before or around the time of diagnosis.[92] Headache is the most
commonly seen CNS finding in SLE, occurring in 39-61% of adults and 72% of children,[92] but it is nonspecific. Altered
mental status in SLE may be secondary to aseptic meningitis, seizures, psychosis, or organic brain syndrome. All types of
seizures have been reported, with the most frequent being grand mal seizure. Sensory or sensorimotor neuropathies occur.

Mononeuritis may manifest as the functional loss of one or a few isolated peripheral nerves and is observed in some
patients with SLE vasculitis or antiphospholipid disease. Deficits below a dermatomal level or spastic paraparesis should
raise consideration of transverse myelitis. Focal neurologic deficits may represent stroke, transient ischemic attack (TIA), or
mononeuritis. The incidence of stroke is high in SLE, and those with antiphospholipid antibodies are at higher risk for such
events.

Cardiopulmonary

Pleuropericardial friction rubs and signs of effusions may be found. Tachypnea, cough, and fever are common
manifestations of lupus pneumonitis. Hemoptysis may signify pulmonary hemorrhage secondary to the disease. However,
infection is the most common cause of infiltrates seen on radiographs. Hemodynamic instability and hypoxia may suggest
pulmonary embolism. Heart failure signs or arrhythmias may point to ischemia or inflammatory myocarditis.

Systolic murmurs are reported in up to 70% of cases. Murmurs may represent Libman-Sacks endocarditis, superimposed
infective endocarditis, thromboembolic disease, or demand-related phenomena in fever, hypoxia, or anemia. Digital infarcts
and splinter hemorrhages may be observed with Libman-Sacks endocarditis. Pulmonary hypertension may be evidenced by
a loud P2 heart sound.

Pulmonary hypertension, vasculitis with digital infarcts, and splinter hemorrhages may be observed.

Pericarditis has an incidence of 20-30% and is the most common presentation of heart involvement clinically, although
examination rubs are less common. It is usually associated with small effusions, but it may involve larger effusions when
uremia is concomitant. Myocarditis can cause heart failure symptoms and arrhythmias.

Gastrointestinal

Occasionally, abdominal tenderness and pain may be linked to peritonitis, pancreatitis, mesenteric vasculitis, or non–lupus-
related processes. Lupus peritonitis is a less-common serositis that may be present, even in the absence of ascites.

Ophthalmologic

Funduscopic examination is important in patients with visual complaints. Slit-lamp examinations are recommended every 6
months for SLE patients who are on hydroxychloroquine to screen for the rare side effect of maculopathy. Retinal vasculitis
can lead to blindness and is demonstrated by sheathed narrow retinal arterioles with white exudates adjacent to the vessels.
SLE-associated optic neuritis is uncommon, but it should be considered in patients with vision loss.[93]

Diagnostic Criteria for SLE


Table 1, below, lists the 1997 update of the American College of Rheumatology (ACR) criteria for the diagnosis of systemic
lupus erythematosus (SLE).[94, 5, 6]

Table 1. Updated American College of Rheumatology Diagnostic Criteria for SLE (Open Table in a new window)

Criterion Definition

SLE can be diagnosed if any 4 or more of the following 11 criteria are present, serially or simultaneously, during any
interval of observation.

1. Malar rash Fixed, flat or raised erythema over the malar eminences, tending to spare the nasolabial folds

Erythematous raised patches with adherent keratotic scaling and follicular plugging (older lesions
2. Discoid rash
may demonstrate atrophic scarring)
3. Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation
Photosensitivity

4. Oral ulcers Oral or nasopharyngeal ulceration, usually painless, observed by a physician

Nonerosive arthritis involving =2 peripheral joints, characterized by tenderness, swelling, or


5. Arthritis
effusion

(A) Pleuritis: Convincing history of pleuritic pain or rub heard by a physician or evidence of pleural
effusion

or
6. Serositis

(B) Pericarditis: Documented by ECG or rub or evidence of pericardial effusion

(A) Persistent proteinuria >0.5 g/day or >3+ if quantitation not performed

or
7. Renal
disorder

(B) Cellular casts: May be red blood cell, hemoglobin, granular, tubular, or mixed

(A) Seizures: In the absence of offending drugs or known metabolic derangements (eg, uremia,
ketoacidosis, electrolyte imbalance)

or
8. Neurologic
disorder

(B) Psychosis: In the absence of offending drugs or known metabolic derangements (eg, uremia,
ketoacidosis, electrolyte imbalance)

9. Hematologic (A) Hemolytic anemia: With reticulocytosis


disorder
or

(B) Leukopenia: < 4000/mm3 total on =2 occasions

or

(C) Lymphopenia: < 1500/mm3 on =2 occasions

or

(D) Thrombocytopenia: < 100,000/mm3 in the absence of offending drugs


(A) Anti-DNA: Antibody to native DNA in abnormal titer

or

(B) Anti-Sm: Presence of antibody to Smith (Sm) nuclear antigen


10.
Immunologic or
disorder

(C) Positive finding of antiphospholipid antibodies based on (1) an abnormal serum level of IgG or
IgM anticardiolipin antibodies, (2) a positive test result for lupus anticoagulant using a standard
method, or (3) a false-positive serologic test for syphilis known to be positive for =6 months and
confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption
tests

An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent assay at any


11. Antinuclear
point in time and in the absence of drugs known to be associated with drug-induced lupus
antibody (ANA)
syndrome

Sources: (1.) American College of Rheumatology. 1997 Update of the 1982 American College of Rheumatology revised
criteria for classification of systemic lupus erythematosus. Available at: http://tinyurl.com/zrfsuhs Accessed: September
19, 2016[94] ; (2.) Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification
of systemic lupus erythematosus. Arthritis Rheum. Sep 1997;40(9):1725.[5]

ECG = electrocardiogram; Ig = immunoglobulin; SLE = systemic lupus erythematosus.

In 2012, the Systemic Lupus International Collaborating Clinics (SLICC) group revised and validated the ACR SLE
classification criteria. The SLICC classification criteria expand the number of criteria from 11 to 17, adding numerous acute
and chronic rashes, as well as alopecia, additional neurologic manifestations, hypocomplementemia, and direct Coomb test
positivity. The SLICC classify a person as having SLE in the presence of biopsy-proven lupus nephritis with ANA or anti–
double-stranded DNA (anti-dsDNA) antibodies or if 4 of their 17 diagnostic criteria, including at least 1 clinical and 1
immunologic criterion.[7]

DDx

Diagnostic Considerations
Before making a diagnosis of systemic lupus erythematosus (SLE), ruling out drugs as the cause of the condition is
important. Many pharmacologic agents have been associated with a lupuslike syndrome (see see Drug-Induced Lupus
Erythematosus), but procainamide, hydralazine, and isoniazid have been studied the most extensively. Many patients who
take these medications have positive antinuclear antibody test results and other serologic findings. Only a few have the
clinical manifestations. Drug-induced lupus differs from SLE by the following features:

Sex ratios are nearly equal

Antibodies to histones are usually found in 80-90%

Nephritis and central nervous system features are not commonly present

There are no antibodies to native DNA or hypocomplementemia


Discontinuation of the drug leads to resolution of clinical manifestations and reversion of abnormal laboratory values
to normal

A syndrome of drug-induced SLE has been observed with minocycline and propylthiouracil. Both drugs have a decreased
frequency of antihistone antibodies and anti–double-stranded DNA antibodies, and results for antineutrophil cytoplasmic
antibodies are sometimes positive. Anti-TNF drugs are reported to cause severe drug-induced lupus, including production of
many SLE autoantibodies and, rarely, even nephritis.[95]

Other problems to be considered in the differential diagnosis of SLE include the following:

Discoid skin lesions

Erythematous macules

Interstitial lung disease

Leukemia

Leukopenia

Parvovirus or other viral infections

Photodistributed rash

Pleuritic chest pain

Pneumonitis

Polyarthritis/polyarthralgia

Renal vasculitis

Seizures

Stroke

Thrombocytopenia

Vasculitis

Differential Diagnoses
Acute Pericarditis

Antiphospholipid Syndrome

Autoimmune Hepatobilliary Disease

B-Cell Lymphoma

Fibromyalgia

Hepatitis C

Epstein-Barr Virus (EBV) Infectious Mononucleosis (Mono)

Infective Endocarditis

Lyme Disease

Mixed Connective-Tissue Disease

Polymyositis

Rheumatoid Arthritis

Scleroderma

Sjogren Syndrome

Undifferentiated Connective-Tissue Disease

Workup
Workup

Approach Considerations
The diagnosis of systemic lupus erythematosus (SLE) must be based on the proper constellation of clinical findings and
laboratory evidence. Familiarity with the diagnostic criteria helps clinicians to recognize SLE and to subclassify this complex
disease based on the pattern of target-organ manifestations.

The 1982 American College of Rheumatology (ACR) criteria summarized features necessary to diagnose SLE.[94, 5] These
criteria were last updated in 1997.[5, 6] The presence of 4 of the 11 criteria yields a sensitivity of 85% and a specificity of
95% for SLE (see Table 1). Keep in mind that individual features are variably sensitive and specific. Patients with SLE may
present with any combination of clinical features and serologic evidence of lupus.

The Systemic Lupus International Collaborating Clinics (SLICC) group revised and validated the ACR SLE classification
criteria in 2012.[7] According to the revision, a patient is classified as having SLE if the patient has biopsy-proven lupus
nephritis with ANA or anti-dsDNA antibodies or if the patient satisfies 4 of the diagnostic criteria (see below), including at
least 1 clinical and 1 immunologic criterion.[7]

Also in 2012, the ACR published “ Guidelines for the Screening, Diagnosis, Treatment and Monitoring of Lupus Nephritis in
Adults,” as well as an evidence report for lupus nephritis.[96]

ACR mnemonic of SLE diagnostic criteria

The following are the ACR diagnostic criteria in SLE, presented in the "SOAP BRAIN MD" mnemonic:

Serositis - Pleurisy, pericarditis on examination or diagnostic electrocardiogram (ECG) or imaging

Oral ulcers - Oral or nasopharyngeal, usually painless; palate is most specific

Arthritis - Nonerosive, 2 or more peripheral joints with tenderness or swelling

Photosensitivity - Unusual skin reaction to light exposure

Blood disorders - Leukopenia (< 4 × 103 cells/µL on >1 occasion), lymphopenia (< 1500 cells/µL on >1 occasion),
thrombocytopenia (< 100 × 103 cells/µL in the absence of offending medications), hemolytic anemia

Renal involvement – Based on presence of proteinuria (>0.5 g/day or 3+ positive on dipstick testing) or cellular casts
(including red blood cells [RBCs], hemoglobin, granular, tubular, or mixed)[96] or based on the opinion of a
rheumatologist or nephrologist[96]

Antinuclear antibodies (ANAs) - Higher titers generally more specific (>1:160); must be in the absence of medications
associated with drug-induced lupus

Immunologic phenomena - dsDNA; anti-Smith (Sm) antibodies; antiphospholipid antibodies (anticardiolipin


immunoglobulin G [IgG] or immunoglobulin M [IgM] or lupus anticoagulant); biologic false-positive serologic test
results for syphilis, lupus erythematosus (LE) cells (omitted in 1997 revised criteria)

Neurologic disorder - Seizures or psychosis in the absence of other causes

Malar rash - Fixed erythema over the cheeks and nasal bridge, flat or raised

Discoid rash - Erythematous raised-rimmed lesions with keratotic scaling and follicular plugging, often scarring

In patients with high clinical suspicion and/or high ANA titers, additional testing is indicated. This commonly includes
evaluation of antibodies to dsDNA, complement, and ANA subtypes such as Sm, SSA, SSB, and ribonucleoprotein (RNP)
(often called the ENA panel), as well as screening anticardiolipin antibodies, lupus anticoagulant, and +/- beta-2
glycoprotein antibodies.

Diagnostic Studies
Standard laboratory studies that are diagnostically useful when systemic lupus erythematosus (SLE) is suspected should
include the following:

Complete blood count (CBC) with differential

Serum creatinine
Urinalysis with microscopy

The CBC count may help screen for leukopenia, lymphopenia, anemia, and thrombocytopenia. Urinalysis and creatinine
studies may be useful to screen for kidney disease.

Other laboratory tests that may be used in the diagnosis of SLE are as follows:

Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)

Complement levels

Liver function tests

Creatine kinase assay

Spot protein/spot creatinine ratio

Levels of inflammatory markers, including the ESR and CRP, may be elevated in any inflammatory condition, including SLE.
However, the level of ESR elevation may show a discrepancy relative to a normal CRP level in SLE flares; if both markers
are markedly elevated, suspect the presence of an infectious process. CRP levels change more acutely, and the ESR lags
behind disease changes.

Measurement of complement may be useful, because C3 and C4 levels are often depressed in patients with active SLE as
a result of consumption by immune complex–induced inflammation. In addition, some patients have congenital complement
deficiency that predisposes them to SLE.

Liver test results may be mildly elevated in acute SLE or in response to therapies such as azathioprine or nonsteroidal anti-
inflammatory drugs (NSAIDS). Creatine kinase levels may be elevated in myositis or overlap syndromes.

The spot protein/spot creatinine ratio may be used to quantify proteinuria. The 2012 ACR guidelines for lupus nephritis
indicate that a spot protein/spot creatinine ratio greater than 0.5 g/day can substitute for the 24-hour protein measurement
and that an active urinary sediment (defined as >5 red blood cells [RBCs] per high-power field [hpf]; >5 white blood cells
[WBCs]/hpf in the absence of infection; or cellular casts limited to RBC or WBC casts) can substitute for cellular casts.[96]

Autoantibody tests

Table 3, below, summarizes the autoantibody tests that are used in the diagnosis of SLE.[97]

Table 3. Autoantibody Tests for SLE (Open Table in a new window)

Test Description

ANA Screening test; sensitivity 95%; not diagnostic without clinical features

Anti-dsDNA High specificity; sensitivity only 70%; level is variable based on disease activity

Anti-Sm Most specific antibody for SLE; only 30-40% sensitivity

Anti-SSA (Ro)
Present in 15% of patients with SLE and other connective-tissue diseases such as Sjögren
or Anti-SSB
syndrome; associated with neonatal lupus
(La)

Anti-ribosomal Uncommon antibodies that may correlate with risk for CNS disease, including increased hazards of
P psychosis in a large inception cohort, although the exact role in clinical diagnosis is debated[98]
Anti-RNP Included with anti-Sm, SSA, and SSB in the ENA profile; may indicate mixed connective-tissue
disease with overlap SLE, scleroderma, and myositis

IgG/IgM variants measured with ELISA are among the antiphospholipid antibodies used to screen
Anticardiolipin
for antiphospholipid antibody syndrome and pertinent in SLE diagnosis

Lupus Multiple tests (eg, direct Russell viper venom test) to screen for inhibitors in the clotting cascade in
anticoagulant antiphospholipid antibody syndrome

Direct
Coombs test–positive anemia to denote antibodies on RBCs
Coombs test

Drug-induced lupus ANA antibodies are often of this type (eg, with procainamide or hydralazine; p-
Anti-histone
ANCA–positive in minocycline-induced drug-induced lupus)

ANA = antinuclear antibody; CNS = central nervous system; ds-DNA = double-stranded DNA; ELISA = enzyme-linked
immunoassay; ENA = extractable nuclear antigen; Ig = immunoglobulin; p-ANCA = perinuclear antineutrophil
cytoplasmic antibody; RBCs = red blood cells; RNP = ribonucleic protein; SLE = systemic lupus erythematosus; Sm =
Smith; SSA = Sjögren syndrome A; SSB = Sjögren syndrome B.

Radiologic Studies
Joint radiography often provides little evidence of systemic lupus erythematosus (SLE), even in the presence of Jaccoud
arthropathy with deformity or subluxations. The most common radiographs in SLE show periarticular osteopenia and soft-
tissue swelling without erosions.

Chest imaging studies include radiography (see the first image below) and computed tomography (CT) scanning (see the
second image below). These modalities can be used to monitor interstitial lung disease and to assess for pneumonitis,
pulmonary emboli, and alveolar hemorrhage.

The chest x-ray from a patient with lupus demonstrates a right-sided pleural effusion (yellow arrow) and atelectasis with
scarring in the left lung base (blue arrow). In severe complications, a fibrothorax may develop.
Vasculitis, antiphospholipid antibodies, and renal failure are commonly found in patients with lupus; these conditions
greatly increase the risk of developing pulmonary emboli. The diagnosis in a patient with shortness of breath, hemoptysis,
and pleuritic chest pain is commonly made with ventilation-perfusion scans or computed tomography (CT) angiography.
The CT angiogram demonstrates a filling defect in the left anterior segmental artery (arrow).

Echocardiography is used to assess for pericardial effusion, pulmonary hypertension, or verrucous Libman-Sacks
endocarditis (see the image below).

Libman-Sacks endocarditis is the most characteristic cardiac manifestation of lupus. It is characterized by clusters of
verrucae on the ventricular surface of the mitral valve. These lesions consist of accumulation of immune complexes,
platelets, and mononuclear cells. This can lead to heart failure, valvular dysfunction, emboli, and secondary infective
endocarditis. Diagnosis is best made via echocardiography, which may reveal the characteristic valvular masses (arrows).
IVS = interventricular septum; LA = left atrium; LV = left ventricle.

Brain magnetic resonance imaging (MRI)/magnetic resonance angiography (MRA) is used to evaluate for central nervous
system (CNS) lupus white-matter changes (see the following image), vasculitis, or stroke, although findings are often
nonspecific and may be absent in as many as 42% of cases with neuropsychiatric symptoms.[99]
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 long-standing systemic lupus erythematosus (SLE). She
presented with headache and subtle cognitive impairments but no motor deficits. Faintly increased signal intensity was
also seen on T1-weighted images, with a trace of enhancement following gadolinium that is too subtle to show on
reproduced images. Distribution of the abnormality is consistent with occlusion of deep penetrating branches, such as
may result from local vasculopathy, with no clinical or laboratory evidence of lupus anticoagulant or anticardiolipin
antibody. Cardiac embolus from covert Libman-Sacks endocarditis remains less likely due to distribution.

Investigators have suggested that cardiac MRI (CMR) provides an excellent alternative to clinical assessment,
electrocardiography, and echocardiography for diagnosing SLE myocarditis.[100] They reported that patients who were
positive for infectious myocarditis on CMR were more symptomatic than those with active SLE disease and that more than
50% of patients with CMR-positive myocarditis had a concurrent positive endomyocardial biopsy.[100]

Joint Effusion and CSF Studies


Arthrocentesis

Arthrocentesis may be performed in patients with joint effusions, which can be inflammatory or noninflammatory. The cell
count may range from less than 25% polymorphonuclear neutrophils (PMNs) in noninflammatory effusions to more than
50% in inflammatory effusions. Viscosity will be high in noninflammatory effusions and low in inflammatory effusions. The
gross appearance of these fluids will be straw-colored or clear in noninflammatory cases and either cloudy or yellow in
inflammatory ones.

Lumbar puncture

Lumbar puncture may be performed to exclude infection with fever or neurologic symptoms. Nonspecific elevations in cell
count and protein level and decrease in glucose level may be found in the cerebrospinal fluid of patients with central
nervous system lupus.

Biopsies and Histologic Features


Renal biopsies

The 2012 American College of Rheumatology (ACR) guidelines for lupus nephritis recommend renal biopsy for all cases of
active, previously untreated lupus nephritis, unless contraindicated.[96] Renal biopsy is used to confirm the presence of
lupus nephritis; to aid in classification of systemic lupus erythematosus (SLE) nephritis based on the International Society of
Nephrology/Renal Pathology Society (ISN/RPS) classification (see Table 4, below); and to guide therapeutic decisions.[96]
Another benefit of renal biopsy is in distinguishing renal lupus from renal vein thrombosis, which may be a complication of
antiphospholipid antibody syndrome and require anticoagulation rather than immunomodulatory therapy.

Renal biopsy is indicated in the presence of the following features[96] :

Increasing serum creatinine in the absence of strong evidence for another etiology (eg, sepsis, hypovolemia,
medication)

Proteinuria of more than 1.0 g per 24 hours, as confirmed by 24-hour urine specimens or spot protein/spot creatinine
ratios

Proteinuria of 0.5 g or more per 24 hours, along with either (1) hematuria (≥5 RBCs/hpf) or (2) cellular casts, as
confirmed by a minimum of 2 tests within a short period and in the absence of alternative causes

The ISN/RPS published revisions to the World Health Organization (WHO) classification for lupus nephritis in 2003. The
classification is based on light microscopy, electron microscopy, and immunofluorescence findings from renal biopsy results,
as summarized in the table below.[101]

Table 4. International Society of Nephrology 2003 Revised Classification of SLE Nephritis (Open Table in a new window)

Class Classification Features

Class Minimal
Normal light microscopy findings; abnormal electron microscopy findings
I mesangial

Class Mesangial
Hypercellular on light microscopy
II proliferative

< 50% of glomeruli involved

Class III lupus nephritis is further subclassified as follows:


Class Focal
Class III (A), focal proliferative: Active lesions
III proliferative
Class III (A/C), focal proliferative and sclerosing: Active and chronic lesions

Class III (C ) (focal sclerosing): Chronic lesions

=50% of glomeruli involved; classified segmental or global; treated aggressively

Class IV lupus nephritis is also further subclassified, as follows:

Class IV-S: Diffuse segmental proliferative

Class Diffuse Class IV-G: Diffuse global proliferative


IV proliferative
Class IV-S or IV-G, active (A) or chronic (C)

Note: It remains to be determined whether further subcategories have a prognostic


difference.[102] There are conflicting data from studies; some investigators report that class
IV-G (A) has a better prognosis relative to class IV-S (A/C), which is less responsive to
treatment.

Class Predominantly nephrotic disease


Membranous
V
Note: Class V may occur with class III or IV (then, both cases would be diagnosed)[96]
Class Advanced =90% of glomeruli involved without residual activity[96]
VI sclerosing
Chronic lesions and sclerosis

Source (except as noted otherwise) : Weening JJ, D'Agati VD, Schwartz MM, et al. The classification of
glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol. Feb 2004;15(2):241-50.[103]

SLE = systemic lupus erythematosus.

Histologic images of a normal renal cortex and of various stages of SLE are shown below.

Histologic image of a normal renal cortex, including the glomerulus (1) and proximal (2) and distal (3) convoluted tubule.
[Image from Wikipedia: http://en.wikipedia.org/wiki/File:Histology-kidney.jpg]

Mesangial proliferative lupus nephritis with moderate mesangial hypercellularity. International Society of
Nephrology/Renal Pathology Society 2003 class II (×200, hematoxylin-eosin).
Focal lupus nephritis. International Society of Nephrology/Renal Pathology Society 2003 class III (×200,
immunofluorescence).

Membranous lupus nephritis showing thickened glomerular basement membrane. International Society of
Nephrology/Renal Pathology Society 2003 class V (×200, silver stain).

Skin biopsies

Skin biopsy can help in diagnosing SLE or unusual rashes in patients with this condition. Many different rashes may herald
SLE, making review by a dermatopathologist important.

Lupus skin rash often demonstrates inflammatory infiltrates at the dermoepidermal junction and vacuolar change in the
basal columnar cells. Discoid lesions demonstrate more-significant skin inflammation, with hyperkeratosis, follicular
plugging, edema, and mononuclear cell infiltration at the dermoepidermal junction. In many SLE rashes, immunofluorescent
stains demonstrate immunoglobulin and complement deposits at the dermoepidermal basement (see the images below).
Lupus band test. Microphotograph of a histologic section of human skin prepared for direct immunofluorescence using an
anti-IgG antibody. The skin is from a patient with systemic lupus erythematosus and shows IgG deposit at 2 different
places: the first is a band-like deposit along the epidermal basement membrane ("lupus band test" is positive); the second
is within the nuclei of the epidermal cells (anti-nuclear antibodies).

Microphotograph of a fixed Hep-2 line cell prepared for indirect immunofluorescence. The preparation was exposed to a
serum of a patient with systemic lupus erythematosus and labeled using a murine anti-human immunoglobulin G (IgG)
antibody. It shows IgG deposit in the nucleus and nonspecific deposit in the cytoplasm.

Treatment

Approach Considerations
Management of systemic lupus erythematosus (SLE) often depends on disease severity and disease manifestations,[8]
although hydroxychloroquine has a central role for long-term treatment in all SLE patients. The LUMINA (Lupus in
Minorities: Nature versus Nurture) study and other trials have offered evidence of a decrease in flares and prolonged life in
patients given hydroxychloroquine, making it the cornerstone of SLE management.[104]

In general, cutaneous manifestations, musculoskeletal manifestations, and serositis represent milder disease, which may
wax and wane with disease activity. These are often controlled with nonsteroidal anti-inflammatory drugs (NSAIDS) or low-
potency immunosuppression medications beyond hydroxychloroquine and/or short courses of corticosteroids. More
prolonged steroid use is generally reserved for patients with involvement of vital organs. For example, central nervous
system involvement and diffuse proliferative renal disease must be recognized as more severe disease manifestations, and
these are often treated with more aggressive immunosuppression. Evidence suggests a relative undertreatment of SLE
patients with end-stage renal disease (ESRD), because the extent of lupus activity may be underestimated.[105]
EULAR recommendations

In 2007, the European League Against Rheumatism (EULAR) released recommendations for the treatment of SLE.[61] In
patients with SLE without major organ manifestations, glucocorticoids and antimalarial agents may be beneficial.[61]
NSAIDs may be used for short periods in patients at low risk for complications from these drugs. Consider
immunosuppressive agents (eg, azathioprine, mycophenolate mofetil, methotrexate) in refractory cases or when steroid
doses cannot be reduced to levels for long-term use.[106]

EULAR recommendations for the management of SLE with neuropsychiatric manifestations support the evaluation and
treatment of these symptoms in the same way as they are evaluated and treated in patients without SLE; if symptoms
persist, management of these symptoms as an extension of SLE should be considered.[83, 61] For example, in patients
with neuropsychiatric manifestations that may have an inflammatory etiology, immunosuppressive agents may be
considered.[61]

Other guidelines

In 2009, an American College of Rheumatology (ACR) Task Force generated a quality indicator set.[107] In 2012, the ACR
published “ Guidelines for the Screening, Diagnosis, Treatment and Monitoring of Lupus Nephritis in Adults,” as well as an
evidence report for lupus nephritis. These and other guidelines are available at the ACR's Clinical Practice Guidelines Web
site.

Adjunctive therapies
Vitamin D insufficiency and deficiency are more common in patients with SLE than in the general population.[108] Vitamin D
supplementation may decrease disease activity and improve fatigue.[109, 110] In addition,supplementation may improve
endothelial function, which may reduce cardiovascular disease.[111, 112, 113]

No diet-based treatment of SLE has been proven effective. Patients with SLE should be reminded that activity may need to
be modified as tolerated. Specifically, stress and physical illness may precipitate SLE flares. Additionally, persons with SLE
should wear sunscreen and protective clothing or avoid sun exposure to limit photosensitive rash or disease flares.

Consultations

The multisystemic nature of SLE often requires involvement of consultants, depending on the organ system involved.
Consultation with any of the following specialists may be necessary:

Rheumatologist
Infectious disease specialist
Neurologist
Pulmonologist
Cardiologist
Gastroenterologist
Nephrologist
Dermatologist
Hematologist
High-risk obstetrician

Biologic DMARD Therapy


Belimumab

The monoclonal antibody belimumab (Benlysta), a B-lymphocyte stimulator–specific inhibitor, has been found to reduce
disease activity and possibly decrease the number of severe flares and steroid use in patients with SLE when used in
combination with standard therapy.[114] In March, 2011, the US Food and Drug Administration (FDA) approved the use of
belimumab in combination with standard therapies (including steroids, nonbiologic DMARDS [eg, hydroxychloroquine,
azathioprine, methotrexate]) to treat active autoantibody-positive SLE.[115] In July 2017, a subcutaneous (SC) formulation
was approved that allows patients to self-administer a once-weekly dose.[162]

Patients of African-American or African descent did not show significant responses to belimumab in phase III post-hoc
analysis, but those studies were not powered to assess for this effect; in a phase II trial, blacks had a greater treatment
response. These results indicate that the benefits of belimumab in SLE patients remain inconclusive and that further
investigation is needed. Patients with severe active lupus nephritis or CNS lupus or patients previously treated with other
biologics or cyclophosphamide have been excluded from participation in early trials.

The SLE Responder Index (SRI) is a tool that was developed following phase II trials and is composed of the following
scores[116] :
SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus: National Assessment– Systemic Lupus
Erythematosus Disease Activity Index)

BILAG (British Isles Lupus Assessment Group)

PGA (physician global assessment)

SRI response is defined by the following[116] :

A 4-point or greater reduction in the SELENA-SLEDAI score

No new BILAG A or no more than 1 new BILAG B domain score

No deterioration from baseline in the PGA by 0.3 or more points.

A multinational phase III study (BLISS-52) that evaluated the efficacy and safety of IV belimumab, in 867 patients with a
minimum SELENA-SLEDAI score of 6, reported that patients given belimumab had significantly higher SRI scores at 52
weeks than did those given placebo.[117] All groups had similar rates of adverse events.

Similarly, a phase III trial of 819 SLE patients who were positive for either antinuclear antibody or anti–double-stranded DNA
at baseline screening found that IV belimumab at 10 mg/kg plus standard therapy resulted in a significantly greater SRI
score (43.2%) than placebo (33.5%) at 1 year (those who received belimumab 1 mg/kg plus standard therapy had a 40.6%
response rate).[118] Overall, the addition of belimumab to standard therapy reduced SLE disease activity and severe flares,
and the medication was well tolerated.[118]

Approval for SC belimumab was based on the BLISS-SC phase III study (n=839), which documented reduction in disease
activity at week 52 in patients receiving belimumab plus standard of care, compared with those receiving placebo plus
standard of care. SRI response with belimumab versus placebo was 61.4% vs 48.4%, respectively (P = 0.0006). In the
belimumab group, both time to and risk of severe flare were improved (median 171 days vs 118 days; P = 0.0004), and
more patients were able to reduce their corticosteroid dosage by ≥25% (to ≤7.5 mg/day) during weeks 40-52 (18.2% vs
11.9%; P = 0.0732), compared with placebo.[163]

Rituximab

B-cell depletion with rituximab (Rituxan) has been used successfully for rheumatoid arthritis, but studies have shown mixed
results for the treatment of SLE. An open study using rituximab showed positive results as rescue therapy for patients with
active SLE who were unresponsive to standard immunosuppressant therapy.[119]

There have also been case reports of patients with severe refractory SLE in which off-label use of rituximab showed benefits
with tolerable safety profiles.[120, 121, 122] For example, in a retrospective study of 115 patients with severe or refractory
SLE, 40% of patients had a complete response and 27% had a partial response, as measured by BILAG scores recorded 6
months after the first rituximab treatment.[123]

However, three placebo-controlled studies, including the Exploratory Phase II/III SLE Evaluation of Rituximab [EXPLORER]
trial and the Lupus Nephritis Assessment with Rituximab [LUNAR] trial,[124, 125] failed to show an overall significant
response. Despite the negative results in these trials, rituximab continues to be used to treat patients with severe SLE
disease that is refractory to standard therapy.

Pharmacologic agents targeting specific pathways such as cytokines and complement, as well as combinations of rituximab
with costimulatory inhibition with anti-CD40L or CTLA-4Ig, may prove to be more effective in treating SLE.[126]

Emergency Department Management


Acute emergencies in patients with systemic lupus erythematosus (SLE) include the following:

Severe neurologic involvement

Systemic vasculitis

Profound thrombocytopenia with a thrombotic thrombocytopenia (TTP)–like syndrome

Rapidly progressive glomerulonephritis

Diffuse alveolar hemorrhage[127]

These conditions may be treated with high-dose intravenous steroids and cytotoxic therapy such as cyclophosphamide.
Strokes, acute myocardial infarctions, and pulmonary emboli occurring as complications of SLE are managed in the same
way as they are in patients without SLE. In patients who present with fever, it may be necessary to limit immunosuppression
to steroids and to empirically treat for an infection until culture results have been received.
In rare cases, diffuse alveolar hemorrhage may require plasma exchange, or profound steroid-refractory thrombocytopenia
may require therapy with intravenous immunoglobulin (IVIG). Catastrophic antiphospholipid antibody syndrome also
requires aggressive acute management.

For more information, see the Medscape Reference article Antiphospholipid Syndrome.

Hospitalization
Fever in patients with systemic lupus erythematosus (SLE) is grounds for hospital admission because of the difficulty of
distinguishing a disease flare from infection in these immunocompromised hosts. Patients with SLE are often complement
deficient and functionally asplenic; therefore, they are at particular risk for infections with encapsulated organisms. For
example, meningococcemia in young females with lupus may be catastrophic.

Although it is known that chronically low complement levels and functional asplenia may result in a low level of susceptibility
to infection, it is not known to what degree.[128, 129] Overall, it is likely that the primary reason patients with SLE die of
infections is immunosuppressive medications.Stress-dose steroid protocols should be used in patients who are receiving
maintenance corticosteroids when they are admitted with infectious or perioperative stress.

Central nervous system lupus with depressed consciousness or alveolar hemorrhage may prompt transfer to an intensive
care unit and consideration of protective intubation. Thrombotic thrombocytopenic purpura and catastrophic antiphospholipid
antibody syndrome should prompt transfer to a center capable of offering plasma exchange therapy.

For more information, see the Medscape Reference articles Neurologic Manifestations of Systemic Lupus Erythematosus
and Thrombotic Thrombocytopenic Purpura.

Lupus Nephritis
The 2012 American College of Rheumatology (ACR) guidelines for lupus nephritis recommend that treatment of this
condition be largely based on classification by the International Society of Nephrology/Renal Pathology Society (ISN/RPS)
histologic criteria (see Biopsies and Histologic Features).[96]

Lupus nephritis is managed with a combination of glucocorticoids[130] and immunosuppressive agents to slow the
progression to end-stage renal disease (ESRD), along with maintaining normal blood pressure levels (ie, target of ≤130/80
mm Hg).[61, 96] In general, individuals with class I or II lupus nephritis do not need management with immunosuppression.
[96]

Patients with class III or IV disease, as well as those with a combination of class V and class III or IV disease, generally
undergo aggressive therapy with glucocorticoid drugs and immunosuppressants.[96] Immunosuppressive therapy consists
of induction and maintenance therapy. Induction therapy involves potent immunosuppressive drugs (eg, mycophenolate
mofetil, cyclophosphamide) to achieve remission; these drugs are generally used for 3 months to 1 year, with an average of
6 months’ treatment having been shown to be more efficacious and safer than long-term therapy.[131]

A large randomized trial that compared induction therapy consisting of oral mycophenolate mofetil with cyclophosphamide
therapy in patients with lupus nephritis showed that mycophenolate mofetil was not inferior to cyclophosphamide.[132] The
investigators suggested that mycophenolate mofetil was associated with both a trend toward greater complete remissions
and a greater safety profile.[132] This study’s findings were confirmed with the large, international Aspreva Lupus
Management Study (ALMS) trial.[133]

Once remission is achieved, start maintenance therapy with azathioprine or mycophenolate mofetil (ie, use less potent
agents relative to long-term cyclophosphamide). The ALMS maintenance trial also found that mycophenolate mofetil was
superior to azathioprine in the maintenance of the renal response to treatment and in the prevention of relapse in patients
with lupus nephritis.[134] In the MAINTAIN trial, there was a trend toward fewer renal flares in patients receiving
mycophenolate mofetil than in those receiving azathioprine[135] ; however, these results did not reach statistical
significance.

When Griffiths et al compared the corticosteroid-sparing effect of cyclosporine with azathioprine in patients with severe SLE,
they concluded that azathioprine may be considered first-line therapy, whereas cyclosporine requires close monitoring of
blood pressure and serum creatinine. However, the investigators noted that in patients who are unable to tolerate
azathioprine, cyclosporine may be considered.[136]

Unfortunately, significant side effects are associated with cyclophosphamide-based regimens, which are the only ones with
proven long-term efficacy. An alternative consideration is mycophenolate mofetil, which may be as effective as pulse
cyclophosphamide but with less severe adverse effects. In refractory cases (lack of treatment response by 6 months),
consider intensifying therapy with mycophenolate mofetil.[61]
In patients with SLE and nephritis who progress to end-stage renal disease, dialysis and transplantation may be required;
these treatments have rates of long-term patient and graft survival that are similar to those observed in patients without
diabetes and SLE.[61] However, transplantation is considered the treatment of choice because of improved survival rates.
[61]

For more information, see Lupus Nephritis.

Adjunctive therapy

Unless contraindicated, hydroxychloroquine should be used as adjunctive therapy in lupus nephritis because of the potential
for reduction in rates of disease flare; damage accrual, ,including renal damage; and risk of thrombotic events.[96]

Administer angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) to all patients with
lupus nephritis (except pregnant women) who have proteinuria of 0.5 g or more per 24 hours (or equivalent by
protein/creatinine ratios on spot urine tests).[96] This treatment has been reported to not only reduce proteinuria by about
30% but also significantly delay the doubling of serum creatinine and the progression to ESRD (in patients with nondiabetic
chronic renal disease).[139]

Statin therapy is recommended in patients with low-density lipoprotein cholesterol (LDL-C) levels greater than 100 mg/dL
because both renal dysfunction alone and SLE alone are independent risk factors for accelerated atherosclerosis.[96]

Antiphospholipid Syndrome
In patients with systemic lupus erythematosus (SLE), the presence of antiphospholipid antibodies is common; depending on
the assay, these antibodies have been reported in up to 30-50% of SLE patients.[137] Therefore, it is important to evaluate
these patients for risk factors for thrombosis, such as use of estrogen-containing drugs, being a smoker, immobility, previous
surgery, and the presence of severe infection or sepsis.[61] The European League Against Rheumatism (EULAR) has noted
that low-dose aspirin in individuals with SLE and antiphospholipid antibodies is potentially useful for primary prevention of
thrombosis and pregnancy loss.[61]

Secondary prevention of thrombosis in nonpregnant patients with SLE and thrombosis associated with antiphospholipid
syndrome can be managed with long-term use of oral anticoagulants.[61] In pregnant patients with SLE and
antiphospholipid syndrome, unfractionated or low-molecular-weight heparin and aspirin may reduce the risk of pregnancy
loss.

For additional information, see Antiphospholipid Syndrome and Systemic Lupus Erythematosus and Pregnancy.

SLE in Pregnancy
Fertility rates in women with systemic lupus erythematosus (SLE) may be similar to those in the general population.
However, the incidence of spontaneous abortion, premature labor, early preeclampsia/eclampsia, fetal growth restriction,
and intrauterine death are somewhat higher in women with SLE,[61, 138] especially in those with SSA(Ro)/SSB(La)
antibodies, antiphospholipid antibodies,[88] or lupus nephritis.[139] One study suggested that women with SLE have fewer
live births than the general population.[140] In this study, decreased live births were associated with exposure to
cyclophosphamide and high SLE disease activity.

SLE can also flare during or after pregnancy. Whether flares of SLE are more frequent during pregnancy is controversial.
The flares do not seem to be exceedingly more serious than those in nonpregnant patients, although pregnancy outcomes
are generally more likely to be complicated. Increased rates of hypertension during pregnancy, premature delivery,
unplanned cesarean delivery, postpartum hemorrhage, and maternal venous thromboembolism are all more frequent in
women with SLE.

To minimize complications in pregnancy, SLE ideally should be well controlled for at least 4-6 months before conception.
Obstetricians who handle high-risk pregnancies should optimally offer pregnancy planning consultation and monitor all
pregnancies in patients with SLE. Suggestions for treatment of SLE during pregnancy are also included in the European
League Against Rheumatism (EULAR) recommendations. High-dose aspirin and NSAIDs should be avoided in later
pregnancy.

The EULAR recommendations indicate that in pregnant women with SLE, prednisolone, azathioprine, hydroxychloroquine
(unnecessary discontinuation of hydroxychloroquine during pregnancy may result in lupus flares), and low-dose aspirin may
be used.[61] Prednisone, prednisolone, and methylprednisolone are the corticosteroids of choice during pregnancy because
of their minimal placental transfer. However, mycophenolate mofetil, cyclophosphamide, and methotrexate are strictly
contraindicated.[61]

Neonatal lupus erythematosus (NLE) can develop in the babies of mothers with antibodies to SSA/Ro. Neonates with NLE
can present with rash around 4-6 weeks of life, elevated liver function test results, thrombocytopenia around 1-2 weeks of
life, neutropenia, and hydrocephalus.[141] NLE can also manifest as a congenital atrioventricular conduction block,[142]
with as many as 1-5% of pregnancies in mothers with anti- SSA/SSB antibodies leading to heart block, rising to a 6-25% risk
for subsequent pregnancies after one affected child is born.[143]

For additional information, see Systemic Lupus Erythematosus and Pregnancy and Neonatal and Pediatric Lupus
Erythematosus.

Prevention
Patients with SLE should be educated to avoid triggers for flare. Persons with SLE should avoid ultraviolet light and sun
exposure to minimize worsening of symptoms from photosensitivity. Diet modification should be based on the disease
activity. A balanced diet is important, but patients with SLE and hyperlipidemia, for example, should be placed on a low-fat
diet. Many patients with SLE have low levels of vitamin D because of less sun exposure; therefore, these patients should
take vitamin D supplements. Exercise is important in SLE patients to avoid rapid muscle loss, bone demineralization, and
fatigue. Smoking should also be avoided.

Antimalarial therapy (hydroxychloroquine) has been shown to prevent disease flares and to decrease mortality.[104] In
contrast, high rates of sulfa allergy and anecdotal reports of disease flares have led to avoidance of sulfa-based medications
in patients with SLE.

Contraception and family planning are important considerations given the risks of disease flare with exogenous estrogens
and pregnancy and with the teratogenic risks of some SLE drugs. Estrogen therapies have typically been avoided to prevent
disease flares; progesterone-only contraception is more often considered.[144] However, studies have suggested that oral
estrogen-containing contraceptives may not be associated with disease flares or thrombosis risk in patients with mild lupus
without antiphospholipid antibodies.[52, 145]

Preventive measures are necessary to minimize the risks of steroid-induced osteoporosis and accelerated atherosclerotic
disease.[146] The American College of Rheumatology (ACR) Guidelines for the prevention of glucocorticoid-induced
osteoporosis suggest the use of traditional measures (eg, calcium, vitamin D) and the consideration of prophylactic
bisphosphonate therapy.

The ACR Quality of Care statement[147] recommends annual cardiovascular disease risk assessment; some researchers
suggest that the cardiovascular risk for SLE is similar to that for diabetes mellitus. The 10-year coronary event rate is 13-
15% in patients with active SLE, which is comparable to the 10-year event rate of 18.8% in patients with known coronary
artery disease.[148] African American patients with SLE may be particularly vulnerable to premature cardiovascular disease
and related death.[149]

Angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers may be useful in patients with renal
disease. Aggressive blood pressure and lipid goals may help prevent CAD or renal disease progression.[148]

The European League Against Rheumatism (EULAR) vaccination recommendations for rheumatic diseases, including
lupus, advocate baseline assessment and delivery of nonlive vaccines during stable disease.[150] Particularly important is
immunization against encapsulated organisms, such as meningococcal vaccine, pneumococcal vaccine, and routine
Haemophilus influenzae childhood vaccination. Annual influenza vaccine is also encouraged.

Long-Term Monitoring
Periodic follow-up and laboratory testing, including complete blood counts with differential, creatinine, and urinalyses, are
imperative for detecting signs and symptoms of new organ-system involvement and for monitoring response and adverse
reactions to therapies. At least quarterly visits are recommended in most cases.[151] Periodic complement levels and
dsDNA titers may be used as adjuncts to clinical evaluation for detecting lupus flares.

Opportunistic infections can develop, most often in patients receiving chronic immunosuppressive therapy. Another less-
common complication is osteonecrosis, especially of the hips and knees after prolonged high-dose corticosteroid usage.
More commonly, premature atherosclerotic disease and myocardial infarction are indolent complications of chronic
inflammation and steroids.

Vitamin D
Studies from around the world have documented a higher prevalence of vitamin D insufficiency and deficiency in patients
with SLE, compared with the general population, especially in conjunction with obesity.[108, 152, 153, 154, 155, 110]
Studies from Australia,[152] France,[155] the Mediterranean region,[109] and Taiwan[154] —but not from Mexico[153] —
have shown an association between serum vitamin D levels and SLE disease activity.
Limited evidence suggests that supplementation may be clinically beneficial in SLE patients with low levels of vitamin D. In
Mediterranean patients, female patients who were not receiving supplemental vitamin D showed more fatigue and received
more oral corticosteroids than those with normal levels of vitamin D.[109] In Australian patients, an increase in serum
vitamin D levels was associated with reduced disease activity over time.[152]

A randomized, double-blind, placebo-controlled trial in 40 patients with juvenile-onset SLE suggests that cholecalciferol
supplementation for 24 weeks is effective in decreasing disease activity and improving fatigue in these patients. Compared
with the placebo group, patients receiving oral cholecalciferol 50,000 IU/week demonstrated significant improvement in
Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores (P = 0.010) and European Consensus Lupus
Activity Measurement (ECLAM) scores (P = 0.006), along with a reduction of fatigue related to social life, as measured
by the Kids Fatigue Severity Scale (K-FSS) score (P = 0.008).[110]

Endothelial dysfunction and increased risk of cardiovascular disease occur in SLE.[111] In vitro and clinical studies have
demonstrated a beneficial effect of vitamin D supplementation on endothelial function in SLE.[112, 113]

Medication

Medication Summary
Treatment of systemic lupus erythematosus (SLE) is guided by the individual patient's manifestations. Fever, rash,
musculoskeletal manifestations, and serositis generally respond to treatment with hydroxychloroquine, nonsteroidal anti-
inflammatory drugs (NSAIDS), and steroids in low to moderate doses, as necessary, for acute flares. Medications such as
methotrexate may be useful in chronic lupus arthritis, and azathioprine and mycophenolate have been widely used in lupus
of moderate severity.[156]

Central nervous system involvement and renal disease constitute more serious disease and often require high-dose steroids
and other immunosuppressive agents, such as cyclophosphamide, azathioprine, or mycophenolate. Class IV diffuse
proliferative lupus nephritis has also been treated with aggressive cyclophosphamide induction therapy.[157, 158] In the
past several years, trials of mycophenolate have demonstrated efficacy for induction, particularly in black patients.[159, 160,
161] Rituximab trials, however, have not documented a benefit with this agent.[124, 125] The MAINTAIN trial offered data
showing no statistically significant difference between mycophenolate and azathioprine for lupus nephritis maintenance.
[135]

Antimalarials

Class Summary
Antimalarial agents may work through numerous proposed mechanisms in SLE, mediating subtle immunomodulation
without causing overt immunosuppression. These drugs are useful in preventing and treating lupus skin rashes,
constitutional symptoms, arthralgias, and arthritis; antimalarials also help to prevent lupus flares and have been associated
with reduced morbidity and mortality in SLE patients followed in observational trials.[104]

Hydroxychloroquine sulfate (Plaquenil)


Hydroxychloroquine inhibits chemotaxis of eosinophils and locomotion of neutrophils and impairs complement-dependent
antigen-antibody reactions. Hydroxychloroquine sulfate 200 mg is equivalent to 155 mg hydroxychloroquine base and 250
mg chloroquine phosphate. Weight-based dose adjustment and monitoring help to mitigate the risk of retinal toxicity. This
agent is also commonly used for suppression and treatment of malaria.

NSAIDs

Class Summary
Nonsteroidal anti-inflammatory agents (NSAIDS) provide symptomatic relief for arthralgias, fever, headache, and mild
serositis. NSAIDs may cause elevated creatinine or liver function test results in patients with active systemic lupus
erythematosus. Additionally, concomitant administration with prednisone may increase the risk of gastrointestinal ulceration.
Ibuprofen (Advil, Motrin)
Ibuprofen is the drug of choice for patients with mild to moderate pain. It inhibits inflammatory reactions and pain by
decreasing prostaglandin synthesis.

Naproxen (Aleve, Anaprox, Naprosyn)


Naproxen is used for relief of mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing activity of the
enzyme cyclooxygenase, resulting in prostaglandin synthesis.

Diclofenac (Voltaren XR, Cataflam)


Diclofenac inhibits prostaglandin synthesis by decreasing activity of enzyme cyclo-oxygenase, which in turn decreases
formation of prostaglandin precursors.

DMARDS, Immunomodulators

Class Summary
Disease-modifying antirheumatic drugs (DMARDS) are immunomodulatory agents that act as immunosuppressives and
cytotoxic and anti-inflammatory medications. The specific agent selection is generally indicated by the patient’s organ
involvement and disease severity. Due to toxicity, cyclophosphamide is reserved for severe organ-threatening disease. At
the other end of the spectrum, methotrexate or azathioprine may be helpful for milder arthritis or skin disease. DMARDS can
be used in patients whose condition has had an inadequate response to glucocorticoids. Azathioprine, mycophenolate, and
cyclosporine have all been studied for lupus manifestations such as nephritis.

Cyclophosphamide
Cyclophosphamide is used for immunosuppression in cases of serious SLE organ involvement, especially severe CNS
involvement, vasculitis, and lupus nephritis. This agent is chemically related to nitrogen mustards. As an alkylating agent,
the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of
normal and neoplastic cells.

Methotrexate (Otrexup, Rasuvo)


Methotrexate is used for managing arthritis, serositis, cutaneous, and constitutional symptoms. It blocks purine synthesis
and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), thus increasing anti-inflammatory adenosine concentration at
sites of inflammation. Methotrexate ameliorates symptoms of inflammation and is particularly useful in arthritis treatment.

Azathioprine (Imuran, Azasan)


Azathioprine is an immunosuppressant and a less toxic alternative to cyclophosphamide. It is used as a steroid-sparing
agent in nonrenal disease. Azathioprine antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. It
may decrease proliferation of immune cells, which results in lower autoimmune activity.

Mycophenolate (CellCept, Myfortic)


Mycophenolate is useful for maintenance in lupus nephritis and other serious lupus cases. This agent inhibits inosine
monophosphate dehydrogenase (IMPDH) and suppresses de novo purine synthesis by lymphocytes, thereby inhibiting their
proliferation. Mycophenolate also inhibits antibody production.

Immune globulin IV (IGIV) (Bivigam, Carimune, Gammagard S/D,


Flebogamma, Gamunex-C)
Intravenous immune globulin is used for immunosuppression in serious SLE flares. It neutralizes circulating myelin
antibodies through anti-idiotypic antibodies. This agent downregulates proinflammatory cytokines, including interferon-
gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells; and augments suppressor T cells.
Immune globulin also blocks complement cascade, promotes remyelination, and may increase cerebrospinal fluid IgG
(10%).
Rheumatologics, Other

Class Summary
Rheumatologic agents such belimumab reduce immune response and B-cell mediated immunity.

Belimumab (Benlysta)
Belimumab inhibits the biologic activity of B-lymphocyte stimulator (BLyS); BLyS is a naturally occurring protein required for
survival and for development of B-lymphocyte cells into mature plasma B cells that produce antibodies. In autoimmune
diseases, elevated BLyS levels are thought to contribute to production of autoantibodies.

This agent is indicated for active, autoantibody-positive SLE that is refractory to standard therapy including
hydroxychloroquine (see Treatment for more details).

Corticosteroids

Class Summary
Corticosteroid agents are used predominantly for anti-inflammatory activity and as immunosuppressants. Preparations
include oral, intravenous, topical, and intra-articular injections.

Methylprednisolone (A-Methapred, Medrol, Solu-Medrol, Depo-Medrol)


Methylprednisolone is used for acute organ-threatening exacerbations. It decreases inflammation by suppressing migration
of polymorphonuclear leukocytes and reversing increased capillary permeability.

Prednisone
Prednisone is an immunosuppressant for treatment of autoimmune disorders. It may decrease inflammation by reversing
increased capillary permeability and suppressing polymorphonuclear neutrophil activity. Prednisone stabilizes lysosomal
membranes and suppresses lymphocytes and antibody production. Low-dose oral prednisone can be used for milder SLE,
but more severe involvement necessitates high doses of oral or intravenous therapy.

DMARDs, Other

Class Summary
Rituximab is a monoclonal antibody and an immunosuppressant that eliminates mature circulating B-cells.

Rituximab (Rituxan)
B-cell depletion with rituximab has been used successfully for rheumatoid arthritis, but it has shown mixed results for the
treatment of SLE. One open study using rituximab reported excellent results as rescue therapy for patients with active SLE
who were unresponsive to standard immunosuppressant therapy. However, 2 large placebo-controlled studies failed to
show an overall significant response. Note that rituximab has an off-label indication for SLE.

Questions & Answers


Overview

Which procedures may be used in the diagnosis of systemic lupus erythematosus (SLE)?

What is systemic lupus erythematosus (SLE)?


What is the typical presentation of systemic lupus erythematosus (SLE)?

What are the signs and symptoms of systemic lupus erythematosus (SLE)?

Which symptoms suggest systemic lupus erythematosus (SLE) in women?

Which physical findings suggest systemic lupus erythematosus (SLE)?

How is systemic lupus erythematosus (SLE) diagnosed?

What are the ACR diagnostic criteria for systemic lupus erythematosus (SLE)?

Which lab studies are used to diagnose systemic lupus erythematosus (SLE)?

Which imaging studies are used to diagnose systemic lupus erythematosus (SLE)?

How is systemic lupus erythematosus (SLE) managed?

Which medications are used in the treatment of systemic lupus erythematosus (SLE)?

What are the characteristics of systemic lupus erythematosus (SLE)?

How is systemic lupus erythematosus (SLE) diagnosed?

Which factors have a role in the pathogenesis of systemic lupus erythematosus (SLE)?

What are the potential mechanisms for development of autoantibodies in systemic lupus erythematosus (SLE)?

What is the role of T cells in the pathogenesis of systemic lupus erythematosus (SLE)?

What is the role of circulating immune complexes in the pathogenesis of systemic lupus erythematosus (SLE)?

Are the presence of autoantibodies a prognostic factor in systemic lupus erythematosus (SLE)?

What is the role of serum antinuclear antibodies (ANAs) in the pathogenesis of systemic lupus erythematosus (SLE)?

Is there a genetic etiology for systemic lupus erythematosus (SLE)?

Which genes cause systemic lupus erythematosus (SLE)?

What role do genes play in the development of systemic lupus erythematosus (SLE)?

What is the etiology of systemic lupus erythematosus (SLE)?

What is the recurrence rate of systemic lupus erythematosus (SLE) in families?

Does systemic lupus erythematosus (SLE) have a genetic predisposition?

Which genes increase the risk of systemic lupus erythematosus (SLE)?

Which human leukocyte antigens (HLAs) may increase the risk for systemic lupus erythematosus (SLE)?

Which infectious agents may be etiologic factors for systemic lupus erythematosus (SLE)?

What are the early-life risk factors for systemic lupus erythematosus (SLE)?

Which environmental factors may have a role in the development of systemic lupus erythematosus (SLE)?

How does pregnancy affect the development of systemic lupus erythematosus (SLE)?

What is the role of vitamin D in the development of systemic lupus erythematosus (SLE)?

What is the incidence and prevalence of systemic lupus erythematosus (SLE) in the US?

Does systemic lupus erythematosus (SLE) have a gender or racial predilection?

What is the global prevalence of systemic lupus erythematosus (SLE)?

How does the prevalence of systemic lupus erythematosus (SLE) vary among different ages, genders, and races?

Is systemic lupus erythematosus (SLE) more common among men or women?

What is the prognosis of systemic lupus erythematosus (SLE)?

How is systemic lupus erythematosus (SLE) disease activity measured?


Which prognostic factors for systemic lupus erythematosus (SLE) have been identified by the EULAR?

What are the mortality rates for systemic lupus erythematosus (SLE)?

What factors have contributed to a decline in the mortality rate for lupus erythematosus (SLE)?

Which comorbidities increase the rates of mortality in patients with systemic lupus erythematosus (SLE)?

What are the common causes of late deaths in individuals with systemic lupus erythematosus (SLE)?

What are the causes of accelerated coronary artery disease in persons with systemic lupus erythematosus (SLE)?

Does race affect the prognosis of systemic lupus erythematosus (SLE)?

What patient education should be given for systemic lupus erythematosus (SLE)?

Which lifestyle changes should be encouraged in patients with systemic lupus erythematosus (SLE)?

Presentation

What is systemic lupus erythematosus (SLE)?

Which symptoms are commonly found in childhood-onset systemic lupus erythematosus (SLE)?

What are the signs and symptoms of systemic lupus erythematosus (SLE)?

What is the most common constitutional symptom of systemic lupus erythematosus (SLE)?

How is the cause of fever and fatigue differentiated in systemic lupus erythematosus (SLE)?

Is weight loss a symptom of systemic lupus erythematosus (SLE)?

What are the musculoskeletal symptoms of systemic lupus erythematosus (SLE)?

Which hand deformities suggest systemic lupus erythematosus (SLE)?

How common is avascular necrosis (AVN) in patients with systemic lupus erythematosus (SLE)?

What are the diagnostic cutaneous symptoms of systemic lupus erythematosus (SLE)?

What are the characteristics of a malar rash due to systemic lupus erythematosus (SLE)?

What are the characteristics of photosensitivity due to systemic lupus erythematosus (SLE)?

What are the characteristics of discoid lupus in systemic lupus erythematosus (SLE)?

What is subacute cutaneous lupus?

Which nonspecific cutaneous symptoms may be present in systemic lupus erythematosus (SLE)?

What are the renal symptoms of systemic lupus erythematosus (SLE)?

What are the diagnostic neuropsychiatric symptoms of systemic lupus erythematosus (SLE)?

Which neuropsychiatric syndromes of systemic lupus erythematosus (SLE) have been identified by the ACR?

How does delirium present in patients with systemic lupus erythematosus (SLE)?

What are the possible central nervous system (CNS) complications of systemic lupus erythematosus (SLE)?

How common are cognitive disorders in patients with systemic lupus erythematosus (SLE)?

What is the most common neurologic comorbidity of systemic lupus erythematosus (SLE)?

How are acute psychiatric episodes diagnosed in patients with systemic lupus erythematosus (SLE)?

What are the pulmonary complications of systemic lupus erythematosus (SLE)?

What is pleuritis in systemic lupus erythematosus (SLE)?

What are the GI symptoms of systemic lupus erythematosus (SLE)?

What are the cardiac symptoms of systemic lupus erythematosus (SLE)?

What are the hematologic symptoms of systemic lupus erythematosus (SLE)?


Which physical findings suggest systemic lupus erythematosus (SLE)?

What does fever indicate in patients with systemic lupus erythematosus (SLE)?

How does the presentation of systemic lupus erythematosus (SLE) differ between men and women?

What is the appearance of malar rash in systemic lupus erythematosus (SLE)?

What is the appearance of photosensitive rash in systemic lupus erythematosus (SLE)?

What is discoid rash in systemic lupus erythematosus (SLE)?

Are painless oral ulcers a symptom of systemic lupus erythematosus (SLE)?

Which cutaneous findings suggest systemic lupus erythematosus (SLE)?

Which musculoskeletal findings suggest systemic lupus erythematosus (SLE)?

How does myositis and fibromyalgia manifest in patients with systemic lupus erythematosus (SLE)?

What are the renal symptoms of systemic lupus erythematosus (SLE)?

What is the most common central nervous system (CNS) finding of systemic lupus erythematosus (SLE)?

What are the cardiopulmonary symptoms of systemic lupus erythematosus (SLE)?

What is the incidence of pericarditis in patients with systemic lupus erythematosus (SLE)?

Which GI findings suggest systemic lupus erythematosus (SLE)?

Which ophthalmologic exams may be useful in patients with systemic lupus erythematosus (SLE)?

What are the updated ACR diagnostic criteria for systemic lupus erythematosus (SLE)?

DDX

How is drug-induced lupus erythematosus differentiated from systemic lupus erythematosus (SLE)?

Which drugs may cause drug-induced systemic lupus erythematosus (SLE)?

Which disorders should be included in the differential diagnosis of systemic lupus erythematosus (SLE)?

What are the differential diagnoses for Systemic Lupus Erythematosus (SLE)?

Workup

What is the basis of a diagnosis of systemic lupus erythematosus (SLE)?

How is systemic lupus erythematosus (SLE) diagnosed?

What are the ACR diagnostic criteria for systemic lupus erythematosus (SLE)?

What testing is indicated in patients with high clinical suspicion of systemic lupus erythematosus (SLE)?

Which standard lab tests are useful in the diagnosis of systemic lupus erythematosus (SLE)?

How is CBC count used in the diagnostic workup of systemic lupus erythematosus (SLE)?

Which lab tests may be used in the diagnosis of systemic lupus erythematosus (SLE)?

What is the role of inflammatory markers in the diagnosis of systemic lupus erythematosus (SLE)?

What is the role of liver testing in the diagnosis of systemic lupus erythematosus (SLE)?

What is the role of spot protein/spot creatinine ratio in the diagnosis of systemic lupus erythematosus (SLE)?

Which autoantibody tests are used in the diagnosis of systemic lupus erythematosus (SLE)?

What is the role of radiography in the diagnosis of systemic lupus erythematosus (SLE)?

What is the role of chest imaging in the diagnosis of systemic lupus erythematosus (SLE)?

What is the role of echocardiography (echo) in the diagnosis of systemic lupus erythematosus (SLE)?

What is the role of MRI in the diagnosis of systemic lupus erythematosus (SLE)?
What is the role of cardiac MRI (CMR) in the diagnosis of systemic lupus erythematosus (SLE)?

What is the role of arthrocentesis in the diagnosis of systemic lupus erythematosus (SLE)?

What is the role of lumbar puncture in the diagnosis of systemic lupus erythematosus (SLE)?

What are the ACR guidelines for renal biopsy in patients with systemic lupus erythematosus (SLE)?

When is renal biopsy indicated in systemic lupus erythematosus (SLE)?

What is the classification of systemic lupus erythematosus (SLE) nephritis?

What are the histologic findings of systemic lupus erythematosus (SLE)?

What is the role of skin biopsy in the diagnosis of systemic lupus erythematosus (SLE)?

Which skin biopsy findings suggest systemic lupus erythematosus (SLE)?

Treatment

What factors are considered in the treatment of systemic lupus erythematosus (SLE)?

What are the EULAR recommendations for treating systemic lupus erythematosus (SLE)?

What are the ACR guidelines for the treatment of systemic lupus erythematosus (SLE)?

What is the role of vitamin D in the management of systemic lupus erythematosus (SLE)?

Which diet and activity modifications are effective in the treatment of systemic lupus erythematosus (SLE)?

What specialist consultations are necessary in the treatment of systemic lupus erythematosus (SLE)?

How is belimumab (Benlysta) used in the treatment of systemic lupus erythematosus (SLE)?

What is the efficacy of belimumab (Benlysta) in the treatment of systemic lupus erythematosus (SLE)?

What is the systemic lupus erythematosus (SLE) Responder Index (SRI)?

How effective is belimumab (Benlysta) in the treatment of systemic lupus erythematosus (SLE)?

How is rituximab (Rituxan) used in the treatment of systemic lupus erythematosus (SLE)?

What is the efficacy of rituximab (Rituxan) in the treatment of systemic lupus erythematosus (SLE)?

Which pharmacologic agents are under investigation for the treatment of systemic lupus erythematosus (SLE)?

What is the presentation of acute emergencies in systemic lupus erythematosus (SLE), and how are they treated?

When is IVIG indicated in the emergency department (ED) management of systemic lupus erythematosus (SLE)?

When is hospitalization indicated for the treatment of systemic lupus erythematosus (SLE)?

When are stress-dose steroid protocols indicated for the treatment of systemic lupus erythematosus (SLE)?

When is admission to the ICU indicated for systemic lupus erythematosus (SLE)?

What are the ACR guidelines for the treatment of systemic lupus erythematosus (SLE) nephritis?

How does the treatment of systemic lupus erythematosus (SLE) nephritis vary depending on the class of disease?

How does oral mycophenolate mofetil compare to cyclophosphamide therapy in the treatment of systemic lupus
erythematosus (SLE) nephritis?

Once remission is achieved in systemic lupus erythematosus (SLE) nephritis, what maintenance therapy should be given?

What are the benefits of mycophenolate mofetil compared to cyclophosphamide-based regimens to treat systemic lupus
erythematosus (SLE) nephritis?

When are dialysis and kidney transplantation indicated in the treatment of systemic lupus erythematosus (SLE) nephritis?

What is the role of hydroxychloroquine in the treatment of systemic lupus erythematosus (SLE) nephritis?

When are ACE inhibitors and ARBs indicated in the treatment of systemic lupus erythematosus (SLE) nephritis?

When is statin therapy indicated in the treatment of systemic lupus erythematosus (SLE) nephritis?
When should patients with systemic lupus erythematosus (SLE) be evaluated for risk of thrombosis?

How does systemic lupus erythematosus (SLE) affect fertility rates?

Are pregnant women at increased risk for systemic lupus erythematosus (SLE) flares?

How are complications minimized in pregnancies of women who have systemic lupus erythematosus (SLE)?

What are the EULAR recommendations for pregnant women with systemic lupus erythematosus (SLE)?

What is neonatal lupus erythematosus (NLE)?

How can systemic lupus erythematosus (SLE) flares be prevented?

Which medication has been shown to prevent disease flares and decrease mortality in systemic lupus erythematosus
(SLE)?

Do oral contraceptives increase the risk of systemic lupus erythematosus (SLE) flares?

What are the ACR guidelines for prevention of osteoporosis in patients with systemic lupus erythematosus (SLE)?

Are ACE inhibitors and ARBs effective in the treatment of systemic lupus erythematosus (SLE) nephritis?

What are the EULAR vaccination recommendations for patients with systemic lupus erythematosus (SLE)?

What long-term monitoring is required for patients with systemic lupus erythematosus (SLE)?

Do vitamin D levels correlate with systemic lupus erythematosus (SLE) disease activity?

Is vitamin D supplementation beneficial for patients with systemic lupus erythematosus (SLE)?

Is cholecalciferol supplementation an effective treatment for systemic lupus erythematosus (SLE)?

Medications

What factors should guide treatment of systemic lupus erythematosus (SLE)?

When are high-dose steroids and other immunosuppressive agents indicated in the treatment of systemic lupus
erythematosus (SLE)?

Which medications in the drug class Antimalarials are used in the treatment of Systemic Lupus Erythematosus (SLE)?

Which medications in the drug class NSAIDs are used in the treatment of Systemic Lupus Erythematosus (SLE)?

Which medications in the drug class DMARDS, Immunomodulators are used in the treatment of Systemic Lupus
Erythematosus (SLE)?

Which medications in the drug class Rheumatologics, Other are used in the treatment of Systemic Lupus Erythematosus
(SLE)?

Which medications in the drug class Corticosteroids are used in the treatment of Systemic Lupus Erythematosus (SLE)?

Which medications in the drug class DMARDs, Other are used in the treatment of Systemic Lupus Erythematosus (SLE)?

Contributor Information and Disclosures

Author

Christie M Bartels, MD, MS Assistant Professor of Rheumatology, Department of Medicine, University of Wisconsin School
of Medicine and Public Health

Christie M Bartels, MD, MS is a member of the following medical societies: American College of Physicians-American
Society of Internal Medicine, American College of Rheumatology

Disclosure: Received research grant from: Independent Grants for Learning and Change (Pfizer).

Coauthor(s)

Daniel Muller, MD, PhD Associate Professor of Medicine, Department of Medicine, Section of Rheumatology, University of
Wisconsin School of Medicine and Public Health

Daniel Muller, MD, PhD is a member of the following medical societies: American Holistic Medical Association, American
College of Physicians-American Society of Internal Medicine, American College of Rheumatology

Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD Visiting Professor of Medicine, Division of Rheumatology, State University of New York Downstate
Medical Center; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital

Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of
Physicians, American College of Rheumatology, American Medical Association, Phi Beta Kappa

Disclosure: Nothing to disclose.

Acknowledgements

Gino A Farina, MD, FACEP, FAAEM Associate Professor of Clinical Emergency Medicine, Albert Einstein College of
Medicine; Program Director, Department of Emergency Medicine, Long Island Jewish Medical Center

Gino A Farina, MD, FACEP, FAAEM is a member of the following medical societies: American Academy of Emergency
Medicine, American College of Emergency Physicians, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Elliot Goldberg, MD Dean of the Western Pennsylvania Clinical Campus, Professor, Department of Medicine, Temple
University School of Medicine

Elliot Goldberg, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians,
and American College of Rheumatology

Disclosure: Nothing to disclose.

Julie Hildebrand, MD Consulting Staff, Department of Internal Medicine, Associated Physicians of Madison, WI

Disclosure: Nothing to disclose.

Richard S Krause, MD Senior Clinical Faculty/Clinical Assistant Professor, Department of Emergency Medicine, University
of Buffalo State University of New York School of Medicine and Biomedical Sciences

Richard S Krause, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of
Emergency Medicine, American College of Emergency Physicians, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Viraj S Lakdawala, MD Clinical Instructor of Emergency Medicine, University of California, San Francisco, School of
Medicine; Attending Physician, San Francisco General Hospital

Viraj S Lakdawala, MD is a member of the following medical societies: American Academy of Emergency Medicine and
American College of Emergency Physicians

Disclosure: Nothing to disclose.

Mark J Leber, MD, MPH Assistant Professor of Emergency Medicine in Clinical Medicine, Weill Cornell Medical College;
Attending Physician, Lincoln Medical and Mental Health Center

Mark J Leber, MD, MPH is a member of the following medical societies: American College of Emergency Physicians and
American College of Physicians

Disclosure: Nothing to disclose.

Carlos J Lozada, MD Director of Rheumatology Fellowship Program, Professor, Department of Medicine, Division of
Rheumatology and Immunology, University of Miami, Leonard M Miller School of Medicine

Carlos J Lozada, MD is a member of the following medical societies: American College of Physicians and American College
of Rheumatology

Disclosure: Pfizer Honoraria Speaking and teaching; Amgen Honoraria Speaking and teaching

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of
Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment


Anuritha Tirumani, MD Research Coordinator, Department of Emergency Medicine, Brooklyn Hospital Center

Disclosure: Nothing to disclose.

Acknowledgements

The authors would like to thank Joanna Wong for assistance in preparation of revisions to this topic.

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