eMedicine Specialties > Rheumatology > Systemic Rheumatic Disease

Systemic Lupus Erythematosus

Author: Christie M Bartels, MD, Instructor of Rheumatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health
Coauthor(s): Daniel Muller, MD, PhD, Department of Internal Medicine, Section of Rheumatology, Associate Professor, University of Wisconsin at Madison
Contributor Information and Disclosures

Updated: Jan 22, 2009

Introduction

Background

Systemic lupus erythematosus (SLE) is a chronic, multifaceted inflammatory disease that can affect every organ system of the body. SLE is protean in its manifestations and follows a relapsing and remitting course. This article addresses what is known regarding the etiology, pathophysiology, clinical features, and treatment of SLE.

Pathophysiology

SLE is an autoimmune disorder characterized by multisystem microvascular 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, racial, hormonal, and environmental factors.^1,2 Many immune disturbances, both innate and acquired, occur in SLE, as illustrated in Image 1.

One proposed mechanism for the development of autoantibodies involves a defect in apoptosis that causes increased cell death and a disturbance in immune tolerance.^3,4,2 The redistribution of cellular antigens during apoptosis leads to a cell-surface display of plasma and nuclear antigens in the form of nucleosomes. Thus, dysregulated (intolerant) lymphocytes begin targeting normally protected intracellular antigens.

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 based on the presence of complexes of nuclear antigens such as DNA, immunoglobulins, and complement proteins at these sites. Serum antinuclear antibodies (ANAs) are found in virtually all individuals with active SLE, and antibodies to native double-stranded DNA (dsDNA) are relatively specific for the diagnosis of SLE.

Frequency

United States

According to a recent report from the National Arthritis Data Working Group, approximately 250,000 Americans have systemic lupus.⁵ The frequency of SLE varies by race and ethnicity, with higher rates reported among black and Hispanic people. The prevalence of SLE is approximately 40 per 100,000 whites in Rochester, Minnesota, versus 100 per 100,000 Hispanic persons in Nogales, Arizona.^6,7

International

Worldwide, the prevalence of SLE varies. Although the prevalence of SLE is high in black persons in the United Kingdom, the disease is rarely reported among blacks who live in Africa.⁸

Mortality/Morbidity

The natural history of SLE varies 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 among persons with isolated skin and musculoskeletal involvement than in those with renal and CNS disease.

SLE carries an average 10-year survival rate that now exceeds 90%.^9,10 Prior to 1955, the 5-year survival rate was less than 50%. 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 CDC, one third 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. In 1976, Urowitz first reported bimodal mortality in early versus late SLE, noting that SLE-related deaths usually occur within the first 5-10 years of symptom onset.¹¹

Infectious complications related to active SLE and immunosuppressive treatment are now the most common cause of death in early active SLE, and accelerated arteriosclerosis is a key cause of late mortality.⁹ The Framingham Offspring Study demonstrated that women aged 35-44 years with SLE were 50 times more likely to develop myocardial ischemia than healthy women.¹² Causes of accelerated coronary artery disease (CAD) in persons with SLE are likely multifactorial, including endothelial dysfunction, inflammatory mediators, corticosteroid-induced atherogenesis, and dyslipidemia associated with renal disease.

Race

Worldwide, the prevalence of SLE appears to vary by race. However, because of different prevalence rates among people of the same race in different geographical locations, a clear conclusion cannot yet be drawn. Low reported rates of SLE in Africa in contrast to a high prevalence in black women in the United Kingdom suggests the importance of environmental influences.⁸ In addition, the influence of race on prognosis has been widely debated. The LUMINA study group examined SLE among black, white, and Hispanic patients in the United States (including Puerto Rico) and reported that both disease activity and poverty predicted higher mortality among racial and ethnic minorities.¹³

Sex

SLE frequently starts in women of childbearing age, and 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.¹⁴ The risk of SLE development in men is similar to that in prepubertal or postmenopausal women. Interestingly, SLE is more common in men with Klinefelter disease than in men without the disease, also supporting a hormonal hypothesis.

Age

A correlation between age and incidence of SLE mirrors peak years of female sex hormone production. The prevalence of SLE is highest among women aged 14-64 years. SLE does not have an age predilection in males.

Clinical

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. The following is an overview of the multitudinous protean manifestations.^15,16

• Constitutional symptoms: Nonspecific 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. Fatigue due to active SLE generally occurs in concert with other clinical and laboratory markers. Fever, another common yet nonspecific symptom of SLE, may also result from many causes, the most common of which include active SLE, infection, and drug fever. Careful history taking may help to differentiate these. 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 anasarca.
• Musculoskeletal symptoms: Joint pain is one of the most common reasons for the initial clinical presentation in patients with SLE. Arthralgia, myalgia, and frank arthritis may involve the small joints of the hands, wrists, and knees. In contrast to rheumatoid arthritis, SLE arthritis or arthralgia may be asymmetrical, with pain that is disproportionate to swelling.
• Dermatological symptoms
  • Cutaneous manifestations of SLE comprise 4 diagnostic criteria and multiple other clues to a potential diagnosis of lupus.
    • The first is malar rash, which is characterized by an erythematous rash over the cheeks and nasal bridge. It lasts from days to weeks and is occasionally painful or pruritic.
    • The second feature is photosensitivity, which may be elicited from patients who are asked if they have any unusual rash or symptom exacerbation after sun exposure.
    • The third feature may be discoid rash. 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.
    • Alopecia is the fourth and often less-specific cutaneous feature of SLE. It often affects the temporal regions or creates a patchlike pattern of hair loss.
  • Other cutaneous manifestations related to but not specific to SLE include Raynaud phenomenon, livedo reticularis, panniculitis (lupus profundus), bullous lesions, vasculitic purpura, telangiectasias, and urticaria.
• Renal features: 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 almost all patients. Glomerular disease usually develops within the first few years of SLE onset and is usually 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.
• Neuropsychiatric features
  • Because of the difficulty in distinguishing causal SLE associations from certain neurological features of the disease, only seizure and psychosis are included among the diagnostic criteria. Psychosis may manifest as paranoia or hallucinations. Delirium represents a spectrum of fluctuating altered consciousness characteristic of SLE. Delirium may be caused by CNS vasculitis, encephalopathy, or the manifestations previously called organic brain syndrome. Seizures related to SLE may be generalized or partial and may precipitate status epilepticus. Aseptic meningitis, myelopathy, optic neuropathy, or other demyelinating disorders may also require urgent evaluation. Transverse myelitis with spastic paraparesis is a rare but serious complication of SLE. The CNS Lupus nomenclature has been revised to catalog many manifestations.^17,18
  • Cognitive disorders may be variably apparent in patients with SLE. Formal neuropsychiatric testing reveals deficits in 21-67% of patients with SLE. Whether this represents true encephalopathy, neurological damage, medication effects, depression, or some other process is unclear. Stroke and transient ischemic attack (TIA) may be related to antiphospholipid antibody syndrome or vasculitis. Migraine headaches may also be linked to antiphospholipid syndrome, although this is less clear. Headache and mood disorders may be the most commonly reported neurologic manifestation of SLE, but cause and effect may be difficulty to distinguish.
  • For additional information on neurologic manifestations of SLE, see the article Systemic Lupus Erythematosus in eMedicine’s Neurology volume.
• Pulmonary features: Pulmonary manifestations of SLE may manifest acutely or indolently, representing many complications. 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. Serositis due to pericardial or pulmonary effusions, pulmonary embolism, lupus pneumonitis, chronic lupus interstitial lung disease, complement-mediated pulmonary leukoaggregation, or infection may be related to lupus disease. Pulmonary hypertension without underlying parenchymal lung disease rarely occurs with symptomatic dyspnea or right-sided heart failure. Most seriously, hemoptysis may herald diffuse alveolar hemorrhage, a rare, acute, life-threatening pulmonary complication of SLE.
• Gastrointestinal features: Gastrointestinal symptoms secondary to primary SLE and adverse effects of medication are common among persons with SLE. Abdominal pain in SLE is significant because it may be directly related to active lupus, including peritonitis, pancreatitis, mesenteric vasculitis, and bowel infarction. Nausea and dyspepsia are common symptoms in patients with active SLE and are sometimes difficult to correlate with objective evidence of gastrointestinal involvement. Jaundice due to autoimmune hepatitis may also occur.
• Cardiac features: Heart failure or chest pain must be carefully examined in patients with SLE. Pericarditis that manifests as chest pain is the most common cardiac manifestation of SLE, manifesting as positional chest pain that is often relieved when the patient leans forward. Myocarditis may occur in SLE with heart failure symptomatology. Coronary vasculitis manifesting as angina or infarction is rarely reported. Libman-Sacks endocarditis is noninfectious but may manifest as symptoms similar to those of infectious endocarditis. More commonly, accelerated ischemic CAD is associated with SLE and may present indolently as atypical anginal equivalents.
• Hematologic features: A history of multiple cytopenias such as leukopenia, lymphopenia, anemia, or thrombocytopenia may suggest SLE, among other etiologies. Leukopenia and, more specifically, lymphopenia are common in SLE; this and hypocomplementemia may predispose persons with SLE to frequent infections. Anemia is occasionally overlooked in young menstruating women. Thrombocytopenia may be mild or part of a thrombotic thrombocytopenic purpura (TTP)–like syndrome or antiphospholipid antibody syndrome. History of recurrent early miscarriages or a single late pregnancy loss may be clues to lupus or isolated antiphospholipid antibody syndrome. A family history of autoimmune disease should also raise further suspicion of SLE.

Physical

As discussed above, 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 Lab Studies. Examination findings are discussed by system.^15,16

• Constitutional/lymph findings: Fever may signal infection or an acute SLE flare. Lymphadenopathy or splenomegaly may be found.
• Cutaneous findings
  • Malar rash describes an erythematous rash over the cheeks and nasal bridge, with classic nasolabial fold sparing, as seen in Image 2.
  • Photosensitive rash is often macular or diffusely erythematous in sun-exposed areas of the face, arms, or hands, as in Image 3.
  • Discoid lesions are plaquelike in character, with follicular plugging, which may create scarring. Again, these may represent limited discoid lupus or SLE.
  • Alopecia in SLE often affects the temporal regions or creates a patchy pattern.
  • Oral ulcers may be noted, with palatal ulcers being most specific for SLE.
  • Many other cutaneous findings are not explicitly diagnostic features of SLE. Livedo reticularis is characterized by a lacy, mottled, erythematous skin pattern that develops in some patients with SLE or antiphospholipid antibody syndrome. Raynaud phenomenon may be observed with blue, white, and red color change at the distal digital tips. Capillaroscopy can be performed with an ophthalmoscope to search for dilated capillary nailfold loops. Panniculitis, bullous lesions, vasculitic purpura, and urticaria are other skin lesions that are sometimes seen in SLE.
• Musculoskeletal findings: Small-joint arthritis of the hands and wrists is the most common musculoskeletal finding in SLE, followed by arthritis of the knees. Pain reports may be out of proportion to synovitis or swelling upon examination. 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 that may manifest as weakness rarely occurs and is more commonly related to overlap syndromes or corticosteroid-induced myopathy. Fibromyalgia, which should be distinguished by myofascial tenderness without weakness, is commonly concomitant with SLE, causing generalized widespread pain, arthralgia, and myalgia.
• Renal findings: Hypertension or hematuria may signal nephritic SLE. Edema of periorbital or peripheral regions and anasarca are common physical findings related to nephrotic syndrome or volume overload with renal failure.
• Neuropsychiatric findings: Altered mental status in SLE may be secondary to aseptic meningitis, seizures, psychosis, or organic brain syndrome. Focal neurological deficits may represent stroke, TIA, or mononeuritis. 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.
• Cardiopulmonary findings: Pleuropericardial friction rubs and signs of effusions may be found. Hypoxia, tachypnea, crackles, or gross hemoptysis may be signs of pneumonitis or diffuse intrapulmonary hemorrhage. Hemodynamic instability and hypoxia may suggest pulmonary embolism. Heart failure signs or arrhythmias may point to ischemia or inflammatory myocarditis. Murmurs may represent Libman-Sacks endocarditis, superimposed infectious endocarditis, or thromboembolic disease.
• Gastrointestinal findings: Abdominal tenderness and pain may be observed in 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.

Causes

Although the specific cause of SLE is unknown, immune-system dysregulation and immune-complex tissue damage at sites such as the skin and kidneys, as well as direct antibody-mediated cytotoxicity that causes thrombocytopenia and hemolytic anemia, are suspected causes. Multiple immune disturbances may predispose to SLE (see Image 1).

Recent reports have synthesized what is known about the mechanisms of SLE disease and genetic associations.^2,19 More than 10 gene loci are known to increase the risk of SLE. A genetic predisposition is supported by the 25% concordance among monozygotic twins versus 2% in dizygotic twins. Studies of the human leukocyte antigens (HLA) reveal that HLA-A1, B8, and 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 also investigated the role of infectious etiologies such as Epstein-Barr virus (EBV) that may also perpetuate autoimmunity. The multitudinous distinct genetic associations suggest complex genetic predisposition and gene environment interactions, perhaps explaining the variable clinical manifestations in persons with SLE.

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