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• Highlights
• Introduction
• Causes
• Risk Factors
• Symptoms
• Complications
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• Treatment for Cutaneous and Mild SLE
• Treatment for Severe SLE
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Systemic lupus erythematosus

Description

An in-depth report on the causes, diagnosis, treatment, and prevention of lupus.

Alternative Names

Lupus

Causes

Systemic lupus erythematosus is a complex disorder that occurs as a consequence of a number of independent processes and factors.

Environmental factors, such as viruses, exposure to chemicals, or sunlight trigger inflammatory or immune activity. This immune activation may begin as an appropriate response to an unwanted "invader." But, because of a combination of genetic factors, an individual with lupus develops an ongoing immune response that does not shut itself off appropriately. This leads to waxing and waning flares of inflammation that can involve various organs of the body, depending on specific features of this self-perpetuating immune response in individual patients.

The exact combination of genes that predispose individuals to SLE may differ somewhat from patient to patient, but probably share certain common features which tend to impair the ability of the body to get rid of immune-triggering particles and which tend to prolong or increase the degree of immune responsiveness to these triggers.

A major characteristic of lupus is that it is an autoimmune response in which immune factors, called autoantibodies, attack the person's own cells. Some autoantibodies are normal in a well-balanced immune system, and serve various roles to help the body dispose of wastes, protect from infectious invaders, and to keep blood vessels clear. In healthy people, autoantibodies tend to be well-regulated and well "masked," or covered up, until needed. Therefore, it is probably the high activity and high detectability of autoantibodies that makes lupus unique, not the fact that they exist.

Many people who have viral syndromes or who are at least 50 years old test positive for the anti-nuclear autoantibody (ANA). Thus, this common screening test for lupus actually identifies an autoantibody which is found in many healthy people. A positive ANA test would never give someone a diagnosis of lupus in the absence of lupus symptoms or other disease features.

The Inflammatory Process and Autoimmunity

The Normal Immune System Response. The inflammatory process is a byproduct of the activity of the body's immune system, which fights infection and heals wounds and injuries:

• When an injury or an infection occurs, white blood cells are mobilized to rid the body of any foreign proteins, such as a virus.
• The masses of blood cells that gather at the injured or infected site produce factors to fight any infections.
• In the process, the surrounding area becomes inflamed and some healthy tissue is injured. The immune system is then called upon to repair wounds by clotting any bleeding blood vessels and initiating fiber-like patches to the tissue.
• Under normal conditions, the immune system has special factors that control and limit this inflammatory process.

The Infection Fighters. B cells and T cells are two important components of the immune system that play a role in the inflammation associated with lupus. Both B cells and T cells belong to a family of immune cells called lymphocytes. Lymphocytes help fight infection.

B cells and T cells are involved in the immune system's response to infection. Antigens are foreign bodies (such as bacteria and viruses) that stimulate the immune system to produce autoantibodies. When a T cell recognizes an antigen it will produce chemicals (cytokines) that cause B cells to multiply and release many immune proteins (antibodies). These antibodies circulate widely in the bloodstream, recognizing the foreign particles and triggering inflammation in order to rid the body of the invasion.

T cells can be further categorized as killer T cells or helper T cells. Killer T cells directly attack antigens, such as viruses and tumor cells. Helper T cells recognize antigens that are presented to them by special types of white blood cells (macrophages), and can stimulate B cells to mount various kinds of attacks on the antigen.

For reasons that are still not completely understood, both the T cells and B cells become overactive in lupus patients. In an immune response, it is normal for the antibody response to change over time, particularly if the first antibodies that are made do not eliminate the invading particles. Little by little, the types of antibodies being made undergo changes in an attempt to better recognize and fight an invader. In lupus, a complex interaction between activated immune cells and an impaired antigen-elimination process leads to a greater than normal range of what the antibodies recognize. Eventually, antibodies are made that recognize more of the body's own tissues in a stronger or more persistent manner than is healthy, and inflammatory responses are mounted in these tissues.

Autoantibodies . In the majority of patients with SLE, antinuclear antibodies (ANA) are detectable. Important research published in 2003 found that such autoantibodies may be present in individuals up to 7 years prior to their developing symptoms of lupus. Some subtypes of ANA are found in lupus patients and only rarely in people without lupus. These include:

• Anti-ds DNA. An autoantibody called anti-double stranded DNA (anti-ds DNA) may play an important role in some lupus patients. A 2001 study suggested that some of these antibodies specifically recognize a protein in the kidney called alpha-actinin, which researchers suspect may also occur in other tissues that are affected by SLE, such as in the skin, joints, and brain. A subset of anti-DNA has also been found to target nerve-cell receptors in the brains of patients with SLE.
• Anti-Sm antibodies. This antibody is found most often in lupus patients of African descent and is almost never detected in people without lupus. Although the antibody is not usually seen in lupus patients, its confirmed presence almost always indicates SLE.

Other autoantibodies found in lupus patients include:

• Anti-Ro (SSA) and Anti-La (SSB). These autoantibodies may be involved in the sun-sensitive rashes experienced by patients with SLE and are also found in association with neonatal lupus syndrome, in which a pregnant mother's antibodies cross the placenta and cause inflammation in the developing child's skin or heart.
• Antiphospholipid antibodies. A quarter to a half of patients with SLE may have these antibodies. They attack blood clotting regulator proteins which stick to phospholipids, fatty compounds found in cell membranes throughout the body. Antiphospholipid antibodies increase the risks for blood clots and may be responsible for narrowing of and irregularities in blood vessels. Antiphospholipid antibodies are linked with miscarriages and other pregnancy complications, strokes, heart attacks and blood clots in almost any part of the body, including kidneys, legs, lungs, and eyes.

Cytokines. Most immune cells secrete or stimulate the production of powerful immune factors called cytokines. In small amounts, cytokines are indispensable for maintaining the balance of the body during immune responses, including:

• Infections
• Injuries
• Tissue repair
• Blood clotting
• Dlearing of debris from inflamed blood vessels
• Other aspects of healing.

If overproduced, however, they can cause serious damage, including dangerous levels of inflammation and cellular injury. Specific cytokines called interferons and interleukins play a critical role in SLE by regulating the secretion of autoantibodies by B cells. Researchers are currently interested in interferon alpha. Some evidence suggests high levels of this cytokine may underlie the autoimmune response in SLE.

Complement. Another immune factor of high interest in SLE is the complement system. This is comprised of more than 30 proteins and is important for defending and regulating the immune response. Inherited deficiencies in certain complement components (C1q, C1r, C1s, C4, and C2) have long been associated with SLE. Deficiencies may contribute to SLE in the following manner:

• The complement system may protect against autoimmune disease by normalizing apoptosis , the natural process by which cells self-destruct. This self-destruction process is an important part of the normal way in which the body cleans out damaged or no longer useful cells. In healthy people, autoantibodies may also play a role in regulating apoptosis so that dangerous antigens are not left in the bloodstream long enough to trigger a more global (dysregulated) immune response.
• Complement components are also necessary for clearing molecular rubble called immune complexes. These are the end product of the battle between autoantibodies and antigens. In the absence of complement, this debris accumulates and is deposited in the kidneys, blood vessels, joints, and other sites where it can cause the immune system to produce inflammation and tissue damage.

Genetic Defects

Researchers estimated that 20 - 100 different genetic factors may be involved in the alterations of the immune system set point that could make a person susceptible to SLE.

• Research published in 2003 identified a particular set of genes, now commonly called the "interferon signature," that is activated by interferon in patients with severe lupus. This discovery may help doctors identify patients at particular risk for severe disease before they develop symptoms.
• A genetic risk factor for lupus in African-American women was identified in 2003. This defect causes increased production of nitric oxide, which may predispose individuals to lupus, and to severe disease in particular.
• Other research has identified defects in genes that regulate apoptosis, the natural process by which cells self-destruct.
• Another study identified an abnormal gene in some patients with SLE that promotes the build-up of immune complexes that can cause kidney damage. HLA (human leukocyte antigen) is a protein that presents antigens to T cells by holding them up from the surface of macrophages or other antigen-presenting cells. There are varieties of HLA molecules that are determined by the genes that are inherited. Small differences in HLA from person to person can determine which antigens are presented in triggering an immune response and how strongly the immune system will respond to these antigens. Among the types of HLA associated with lupus are HLA-DR2, -DR3, -A1, -B8, and DMA-0104.

Triggers of the Immune Response

In genetically susceptible people, there are various external factors that can provoke an immune response. Possible SLE triggers include colds, fatigue, stress, chemicals, sunlight, and certain drugs.

Viruses. Blood tests reveal that patients with SLE are more likely to have been exposed to certain viruses than the general population. These viruses include the Epstein-Barr virus (the cause of mononucleosis), cytomegalovirus, and parvovirus-B1.

Results from a 2005 study, conducted by researchers at the National Institute of Environmental Health Sciences, suggested a strong association between Epstein-Barr virus (EBV) and increased risk of lupus, particularly for African-Americans. The study of 230 patients with lupus and matched controls assessed the seroprevalence of EBV antibodies. One particular antibody, EBV-IgA, was linked to a five times greater risk of SLE in African-Americans. The association was not as strong for whites, but increased with age (patients over 50 years of age had four times higher risk).

The researchers also observed that a genetic variation in CTLA-4, a protein that helps regulate T cell immune system response, appeared to modify the risk of lupus associated with EBV-IgA antibodies. The Epstein-Barr virus settles into B cells after initial infection and can become dormant for long periods of time. T cells trigger an immune response and help fight reactivation of infection. Therefore, an individual’s CTLA-4 genotype could determine the immune system’s responsiveness in fighting repeat episodes of EBV infection.

Some research suggests that different viruses may imprint specific types of SLE. For instance cytomegalovirus may affect blood vessels and cause problems such as Raynaud's phenomenon or blood abnormalities, but may not affect the kidney as much. These are speculations, however, and not a proven association.

Sunlight. Ultraviolet (UV) rays found in sunlight are important SLE triggers. When they bombard the skin, they can alter the structure of DNA in cells below the surface. The immune system may perceive these altered skin cells as foreign and trigger an autoimmune response against them. UV light is categorized as UVB or UVA depending on the length of the wave.

• UVB are short waves (280 - 320 nm). The shorter the wavelengths, the more damage they do.
• UVA are longer waves (320 - 400 nm). Some research suggests that UVA wavelengths in the longest range, known as UVA1 (340 - 400 nm), may actually repair DNA and normalize immune responses.

Chemicals. Clusters of SLE cases have occurred in populations with high exposure to certain chemicals. For example, in a 2001 study, citizens in a small town in Arizona had two to seven times the prevalence of SLE, which was associated with a high exposure to chlorinated pesticides. Crystalline silica is another suspect. A number of other chemicals are under investigation. However, it is very difficult to determine a causal role for any specific chemicals. (Silicone breast implants have been under intense scrutiny as a possible trigger of autoimmune diseases, including SLE. The weight of evidence to date, however, finds no support for this concern.) Some drugs have been associated with a temporary lupus syndrome (drug-induced lupus), which resolves when these drugs are stopped.

Hormones. Cytokines, major immune factors that are active in SLE, are directly affected by sex hormones. In general, estrogen enhances antibody production, and testosterone reduces antibody production, although their exact role in SLE may be more complicated than that since there are various ways in which each hormone might influence various immune cells. Women with SLE may have lower levels of several active male hormones (androgens), and some men who are affected by SLE may also have abnormal androgen levels.

Oral Contraceptives . Female patients with lupus used to be cautioned against taking oral contraceptives (OCs) due to the possibility that estrogen could trigger lupus flare-ups. However, recent evidence indicates that OCs are safe, at least for women with inactive or stable lupus. Women who have been newly diagnosed with lupus should avoid OCs. Lupus can cause complications in its early stages. For this reason, women should wait until the disease reaches a stable state before taking OCs. In addition, women who have a history of, or are at high risk for blood clots, (particularly women with antiphospholipid syndrome) should not use OCs. The estrogen in OCs increases the risk for blood clots.

• Review Date: 1/2/2007
• Reviewed By: Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.

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