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Systemic Lupus Erythematosus (SLE)

  • Author: Christie M Bartels, MD, MS; Chief Editor: Herbert S Diamond, MD  more...
 
Updated: Sep 25, 2015
 

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) 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 results
  • 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:

  • Biologic DMARDs (disease-modifying antirheumatic drugs): Belimumab, rituximab, IV immune globulin
  • Nonbiologic DMARDS: Cyclophosphamide, methotrexate, azathioprine, mycophenolate, cyclosporine
  • Nonsteroidal anti-inflammatory drugs (NSAIDS; eg, ibuprofen, naproxen, diclofenac)
  • Corticosteroids (eg, methylprednisolone, prednisone)
  • Antimalarials (eg, hydroxychloroquine)

See Treatment and Medication for more detail.

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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 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.
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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 geneti 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]

Genetic studies also point to disruptions in lymphocyte signaling, interferon response, clearance of complement and immune complexes, apoptosis, and DNA methylation.[25] Genome-wide association studies (GWAS) have identified several loci with a strong association with SLE, many of which 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). Several genes associated with T-cell function and signaling have also 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).[26]

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.[27] 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.[27]

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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 geneti 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.[28] 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.[28]

Some studies have synthesized what is known about the mechanisms of SLE disease and genetic associations.[10, 25, 29] At least 35 genes are known to increase the risk of SLE.[25] 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.[25, 29]

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.[30] 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.[30]

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.[31] 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.[32] 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. They potentially 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.
  • Breastfeeding is associated with a decreased 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. [33]

The results of one study suggest that low vitamin D levels increase autoantibody production in healthy individuals; vitamin D deficiency was also linked to B-cell hyperactivity and interferon-alpha activity in patients with SLE.[34]

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Epidemiology

United States statistics

The annual incidence of SLE averages 5 cases per 100,000 population. The Centers for Disease Control and Prevention (CDC) estimates a range between 1.8 and 7.6 per 100,000 persons per year in the continental United States.[35]

The reported prevalence ranges from 52 cases per 100,000 population[36] —which is consistent with the 2005 CDC estimates of 161,000 definite cases and 322,000 probable or definite SLE cases in the United States[35] —to estimates as high as 1:1000 .

The Lupus Foundation of American estimates prevalence to be up to 1.5 million cases,[37] which likely reflects inclusion of milder forms of this disease. According to a 2008 report from the National Arthritis Data Working Group, approximately 250,000 Americans have definite SLE.[38]

The frequency of SLE varies by race and ethnicity, with higher rates reported in blacks and Hispanics. The prevalence of SLE is approximately 40 per 100,000 whites in Rochester, Minnesota, and 100 per 100,000 Hispanics in Nogales, Arizona.[39, 40] The incidence of SLE in black women is approximately 4 times higher than that in white women. SLE is also more frequent in Asian women than in white women.[39]

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.[36] 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.[41]

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.[41] In general, black women have a higher rate of SLE than women of any other race, followed by Asian women and then white women.[36]

In the United States, black women are 4 times more likely to have SLE than white women.[36] A review of SLE across Asia-Pacific countries revealed considerable variation in prevalence and survival rates.[42] 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.[42]

Female-to-male ratio

More than 90% of cases of SLE occur in women, frequently starting at childbearing age.[31, 43] 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.[44] 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.[45]

The female-to-male ratio peaks at 11:1 during the childbearing years.[46] 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.[47]

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.[48]

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.[49] This effect is likely due to loss of the estrogen effect in older females.

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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[50] and CNS disease.[51] 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.[52]

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 2007 European League Against Rheumatism (EULAR) recommendations included the following[53] :

  • 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.[54] Prior to 1955, the 5-year survival rate in SLE was less than 50%; currently, the average 10-year survival rate exceeds 90%,[55, 51] and the 15-year survival rate is approximately 80%.[56] 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%,[57, 58] 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.[35]

The European League Against Rheumatism (EULAR) task force also identified the following comorbidities as increasing the risk of morbidity and mortality in patients with SLE[53] :

  • 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.[59] 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.[60]

Late deaths (after age 35 years) are generally from myocardial infarction or stroke secondary to accelerated atherosclerosis[54, 61, 55, 62] ; 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.[61] The presence of lupus nephritis may increase these risks.[63] 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.[64] 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.[65]

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.[66]

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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.

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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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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.
Discoid lupus erythematosus.
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.
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.
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.
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.
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).
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).
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.
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]
Table 1. Updated American College of Rheumatology Diagnostic Criteria for SLE
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
2. Discoid rash Erythematous raised patches with adherent keratotic scaling and follicular plugging (older lesions may demonstrate atrophic scarring)
3. Photosensitivity Skin rash as a result of unusual reaction to sunlight, by patient history or physician 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/day or >3+ if quantitation not performed



or



(B) Cellular casts: May be red blood cell, hemoglobin, granular, tubular, or mixed
8. Neurologic disorder (A) Seizures: In the absence of offending drugs or known metabolic derangements (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 disorder (A) Hemolytic anemia: With reticulocytosis



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



or



(B) Anti-Sm: Presence of antibody to Smith (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 =6 months and confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption tests
11. Antinuclear antibody (ANA) An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent assay at any point in time and in the absence of drugs known to be associated with drug-induced lupus 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/1997SLEcriteria Accessed: March 15, 2012[86] ; (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.



Table 3. Autoantibody Tests for SLE
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) or Anti-SSB (La) Present in 15% of patients with SLE and other connective-tissue diseases such as Sjögren syndrome; associated with neonatal lupus
Anti-ribosomal P Uncommon antibodies that may correlate with risk for CNS disease, including increased hazards of psychosis in a large inception cohort, although the exact role in clinical diagnosis is debated[90]
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
Anticardiolipin IgG/IgM variants measured with ELISA are among the antiphospholipid antibodies used to screen for antiphospholipid antibody syndrome and pertinent in SLE diagnosis
Lupus anticoagulant Multiple tests (eg, direct Russell viper venom test) to screen for inhibitors in the clotting cascade in antiphospholipid antibody syndrome
Direct Coombs test Coombs test–positive anemia to denote antibodies on RBCs
Anti-histone Drug-induced lupus ANA antibodies are often of this type (eg, with procainamide or hydralazine; p-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.
Table 4. International Society of Nephrology 2003 Revised Classification of SLE Nephritis
Class Classification Features
Class I Minimal mesangial Normal light microscopy findings; abnormal electron microscopy findings
Class II Mesangial proliferative Hypercellular on light microscopy
Class III Focal proliferative < 50% of glomeruli involved



Class III lupus nephritis is further subclassified as follows:



  • Class III (A), focal proliferative: Active lesions
  • Class III (A/C), focal proliferative and sclerosing: Active and chronic lesions
  • Class III (C ) (focal sclerosing): Chronic lesions
Class IV Diffuse proliferative =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 IV-G: Diffuse global 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.[94] 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 V Membranous Predominantly nephrotic disease



Note: Class V may occur with class III or IV (then, both cases would be diagnosed)[88]



Class VI Advanced sclerosing =90% of glomeruli involved without residual activity[88]



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.[95]



SLE = systemic lupus erythematosus.



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