Systemic Lupus Erythematosus

Author: Mark J Leber, MD, MPH, FACEP, Attending Physician and Faculty, Department of
Emergency Medicine and Residency Program, Lincoln Medical and Mental Health Center
Coauthor(s): Viraj S Lakdawala, MD, Resident Physician, Department of Emergency Medicine,
Lincoln Medical and Mental Health Center, Bronx, NY

Introduction

Background

Systemic lupus erythematosus (SLE) is a multiorgan system autoimmune disease with numerous
immunological and clinical manifestations. It is characterized by an autoantibody response to nuclear
and cytoplasmic antigens. The disease mainly involves the skin, joints, kidneys, blood cells, and
nervous system. Diagnosing and managing SLE in the emergency department can be very challenging
if it is not considered in one's differential diagnosis. Also, the laboratory testing of SLE may be
unavailable on an emergent basis.

Pathophysiology

Systemic lupus erythematosus (SLE) is a multifactorial disease involving genetic, environmental, and
hormonal factors. Its precise pathogenesis is unclear. There is growing evidence in favor of a
clearance deficiency of apoptotic cells as the core mechanism in the pathogenesis of SLE.1 Defective
clearance of apoptotic cells causes secondary necrosis with release of intracellular content and
inflammatory mediators. Macrophages respond and present self-antigens to T and B cells.

Pathogenic autoantibodies are the primary cause of tissue damage in patients with lupus. The
production of these antibodies arises by means of complex mechanisms involving every key facet of
the immune system. The abnormal cellular and humoral response to the formation of these
autoantibodies is modulated by genetic, environmental, and hormonal factors:

• Genetic factors
o Genes of the MHC HLA-A1, B8, and DR3 have been linked to lupus.
o Genetic deficiency of complement factors C1q, C2, or C4
• Environmental factors
o Occupational exposure - Silica, pesticides, mercury
o Drugs - Many drugs have been implicated in drug-induced lupus.
o Sunlight
• Epstein-Barr virus (EBV) has also been identified as a possible factor in the development of
lupus.3

Frequency

United States

In the United States, the annual incidence of systemic lupus erythematosus (SLE) averages 5.1 per
100,000 per year. The incidence of SLE in black women is approximately 4 times higher than in
white women. SLE is more frequent in Asian women than in white women.

The reported prevalence of SLE in the population is 52 cases per 100,000.5

The frequency of SLE could be increasing due to mild forms of the disease that are being recognized.

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International

The highest prevalences of systemic lupus erythematosus (SLE) were reported in Italy, Spain,
Martinique, and the UK Afro-Caribbean population. SLE is more common in women with West
African ancestry who have emigrated from their home area, suggesting that there may be an
environmental trigger as well as a genetic basis for their disease.

Mortality/Morbidity

The life expectancy of such patients has improved from an approximate 4-year survival rate of 50% in
the 1950s to a 15-year survival rate of 80% today. A patient in whom SLE is diagnosed by age 20
years still has a 1 in 6 chance of dying within 15 years, most often from lupus or infection.7 After 35,
the patient is more likely to die from myocardial infarction or stroke.7

Infectious diseases have emerged as one of the leading causes of morbidity and mortality, accounting
for 29% of all deaths in these patients.

Women with SLE between 35 and 44 years of age had a 52-fold higher risk of having a myocardial
infarction than matched women from the Framingham cohort.

Ten-year survival rates in other countries in Asia and Africa are significantly lower, ranging from 60-
70%.10,11,12

Race

Black women have a higher rate of SLE than any other race, followed by Asians, then white women.5

In the United States, black women are 4 times more likely to have SLE than white women.

Sex

For all ages, the female-to-male ratio is 7:1 and 11:1 during the childbearing years.

Age

Onset of systemic lupus erythematosus (SLE) is usually after puberty, typically in the 20s and 30s.

Twenty percent of all cases of lupus are diagnosed during the first 2 decades of life.

Clinical

History

The triad of fever, joint pain, and rash in a woman of childbearing age should suggest the diagnosis of
systemic lupus erythematosus (SLE). These 3 symptoms are some of the most commonly found
symptoms in patients presenting with SLE.

The American College of Rheumatology last updated the diagnostic criteria for SLE in 1997. The
most current criteria are listed below.

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Table

Criterion Definition
1. Malar rash Fixed erythema, flat or raised, over the malar eminences, tending to spare the
nasolabial folds
2. Discoid rash Erythematous raised patches with adherent keratotic scaling and follicular plugging
(Atrophic scarring may occur in older lesions)
3. Skin rash as a result of unusual reaction to sunlight, by patient history or physician
Photosensitivity observation
4. Oral ulcers Oral or nasopharyngeal ulceration, usually painless, observed by a physician
5. Arthritis Nonerosive arthritis involving ≥2 peripheral joints, characterized by tenderness,
swelling, or effusion
6. Serositis (A) Pleuritis: Convincing history of pleuritic pain or rub heard by a physician or
evidence of pleural effusion
or
(B) Pericarditis: Documented by ECG or rub or evidence of pericardial effusion
7. Renal disorder (A) Persistent proteinuria >0.5 g/d or >3+ if quantitation not performed
or
(B) Cellular casts: May be red blood cell, hemoglobin, granular, tubular, or mixed
8. Neurologic (A) Seizures: In the absence of offending drugs or known metabolic derangements
disorder (eg, uremia, ketoacidosis, electrolyte imbalance)
or
(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
10. Immunologic (A) Anti-DNA: Antibody to native DNA in abnormal titer
disorder or
(B) Anti-Sm: Presence of antibody to Sm nuclear antigen
or
(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 at least 6 months and confirmed by Treponema
pallidum immobilization or fluorescent treponemal antibody absorption tests
11. Antinuclear An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent
antibody assay at any point in time and in the absence of drugs known to be associated with
drug-induced lupus syndrome
A person can be diagnosed with SLE if any 4 or more of the 11 criteria are
present, serially or simultaneously, during any interval of observation.
Criterion Definition
1. Malar rash Fixed erythema, flat or raised, over the malar eminences, tending to spare the
nasolabial folds
2. Discoid rash Erythematous raised patches with adherent keratotic scaling and follicular plugging
(Atrophic scarring may occur in older lesions)
3. Skin rash as a result of unusual reaction to sunlight, by patient history or physician
Photosensitivity observation

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4. Oral ulcers Oral or nasopharyngeal ulceration, usually painless, observed by a physician
5. Arthritis Nonerosive arthritis involving ≥2 peripheral joints, characterized by tenderness,
swelling, or effusion
6. Serositis (A) Pleuritis: Convincing history of pleuritic pain or rub heard by a physician or
evidence of pleural effusion
or
(B) Pericarditis: Documented by ECG or rub or evidence of pericardial effusion
7. Renal disorder (A) Persistent proteinuria >0.5 g/d or >3+ if quantitation not performed
or
(B) Cellular casts: May be red blood cell, hemoglobin, granular, tubular, or mixed
8. Neurologic (A) Seizures: In the absence of offending drugs or known metabolic derangements
disorder (eg, uremia, ketoacidosis, electrolyte imbalance)
or
(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
10. Immunologic (A) Anti-DNA: Antibody to native DNA in abnormal titer
disorder or
(B) Anti-Sm: Presence of antibody to Sm nuclear antigen
or
(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 at least 6 months and confirmed by Treponema
pallidum immobilization or fluorescent treponemal antibody absorption tests
11. Antinuclear An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent
antibody assay at any point in time and in the absence of drugs known to be associated with
drug-induced lupus syndrome
A person can be diagnosed with SLE if any 4 or more of the 11 criteria are
present, serially or simultaneously, during any interval of observation.

Physical

• Fever is a challenging problem in systemic lupus erythematosus (SLE). It can be a

manifestation of active lupus or a representation of infection, malignancy, or drug reaction.
Lower-grade temperature is observed in patients on immunosuppressive agents.
o Patients with fever need to have infectious causes ruled out — both viral and
bacterial. Patients with SLE who are on immunosuppressive therapy are at a higher
risk of death due to viruses (ie, herpes simplex virus [HSV], cytomegalovirus [CMV],
varicella-zoster virus [VZV]) and should be treated accordingly if a viral illness is
suspected.
o An infection can mimic a lupus flare and delays in diagnosis and institution of
treatment result in increased mortality.
• Malar rash is a fixed erythema that spares the nasolabial folds. It is a butterfly rash that can be
flat or raised over the cheeks and bridge of the nose. It also often involves the chin and ears.

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 • 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. Systemic manifestations of SLE may be absent.
• Alopecia or loss of hair may occur.
• Lupus should be considered in all patients who experience painless or painful oral or vaginal
ulcers.
• Gastrointestinal findings include vague abdominal discomfort, nausea, and diarrhea. Acute
crampy abdominal pain, vomiting, and diarrhea may signify vasculitis of the intestine.
• Joint findings
o Tenderness, edema, and effusions accompany a polyarthritis that is symmetric,
nonerosive, and usually nondeforming. The arthritis frequently involves the proximal
interphalangeal (PIP) and metacarpophalangeal (MCP) joints of the hands as well as
the wrists and knees.
o Consider avascular necrosis, which is common in patients who are taking
glucocorticoids.
o In addition, consider septic arthritis when one joint is inflamed out of proportion to all
other joints.
• Central nervous system findings
o All types of seizures have been reported; the most frequent is the grand mal seizure.
Sensory or sensorimotor neuropathies are also common.
o Incidence of stroke is high in the first 5 years of disease. Patients with
antiphospholipid antibodies are at higher risk for such events.
• Funduscopic examination is important in patients with visual complaints. Retinal vasculitis
can lead to blindness and is demonstrated by sheathed narrow retinal arterioles with white
exudates adjacent to the vessels.
• The renal system can be affected leading to renal failure. Specific signs and symptoms of
renal disease may not be apparent until advanced nephrotic syndrome or renal failure is
present; therefore, obtaining a urine analysis and serum BUN and creatinine levels on a
regular basis is important.
• Cardiovascular system findings
o Atherosclerosis occurs prematurely in patients with SLE and is an independent risk
factor for cardiovascular disease.
o Pulmonary hypertension, vasculitis with digital infarcts, and splinter hemorrhages
may be observed.
o Systolic murmurs are reported in up to 70% of cases. They may be secondary to
fever, hypoxia, anemia, or Libman-Sacks endocarditis (associated with
antiphospholipid antibodies).
o Pericarditis has an incidence of 20-30% and is the most common presentation of heart
involvement. It is usually associated with small effusions, but it may involve larger
effusions when uremia is concomitant. Myocarditis can cause heart failure,
arrhythmias, and sudden death.
• Pulmonary findings
o Tachypnea, cough, and fever are common manifestations of lupus pneumonitis.
o Hemoptysis may signify pulmonary hemorrhage secondary to the disease. However,
infection is the most common cause of infiltrates seen on radiographs.

Causes

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• Many of the clinical manifestations of systemic lupus erythematosus (SLE) are caused by the
effects of circulating immune complexes on various tissues or to the direct effects of
antibodies to cell surface components.
• Whether polyclonal B-cell activation or a response to specific antigens exists is unclear.
• Cytotoxic T cells and suppressor T cells (which would normally downregulate 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 models.
• A high concordance rate (14-57%) of SLE is noted in monozygotic twins. Each patient
manifests his or her disease differently.
• Five to twelve percent of relatives of patients with SLE have the disease.
• If a mother has SLE, her daughter's risk of developing the disease is 1:40, and her son's risk is
1:250.
• Administration of estrogen to postmenopausal women appears to double the risk of
developing SLE.
• Breastfeeding is associated with a decreased risk of developing SLE.
• Viruses, for example, may stimulate specific cells in the immune network. Patients with SLE
also have higher titers of antibodies to Epstein-Barr virus (EBV), have increased circulating
EBV viral loads, and make antibodies to retroviruses, including to protein regions
homologous to nuclear antigens.
• Trypanosomiasis or mycobacterial infections may induce anti-DNA antibodies or even
lupuslike symptoms, and lupus flares may follow bacterial infections.
• Silica dust and cigarette smoking may increase the risk of developing SLE.
• Photosensitivity is clearly a precipitant of skin disease.
• The presence of antiphospholipid antibodies causes physical signs of thrombosis.