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What is lupus?
Lupus is an autoimmune disease caused by anti-DNA antibodies that attack the body's own healthy cells. The disease is characterized by constant IgG production directed at self antigens in all nucleated cells (Janeway, 1999). This leads to inflammation and damage of body tissues and the common symptoms of fatigue, painful or swollen joints, unexplained fever, skin rashes, and kidney problems. In accordance with the pain in the joints and muscles that results from lupus, the disease has been classified as a rheumatic disease. Lupus is used as a broad term to describe several forms of the disease, but is most often used to refer to systemic lupus erythematosus (SLE), which can effect various parts of the body and cause an array of symptoms. Lupus affects over one million individuals and 90% of those affected are women. People of all races may get lupus; however, lupus is three times more common in black women than in white women. As many as 1 in 250 young black women will get the disease (NIAMS, 1999).The disease received its name in 1851 based on the definitions of lupus ("wolf") and erythematosus ("redness") and the appearance of facial rashes that looked like the bite of a wolf on individuals that had this disease (NIAMS, 1999).
Figure 1: This is a picture of a typical malar rash, also called a "butterfly" rash, that appears on patients with lupus. Permission to use this figure is pending from the author of the website and will be removed if permission is not granted. Click here to go to the website that contains this picture.
What are the types of infection in SLE?
There are two major categories of lupus. The first category includes infections caused by organisms, which can induce infection in those infected with lupus as well as within the general population. These organisms include streptococcus and staphylococcus.
The second category consists of infections are caused by organisms that have the potential for inducing disease only when ones immune system is weakened. Most opportunistic infections are fungal, parasitic or protozoan. The most common infections that lupus patients contract involve the respiratory tract, skin and urinary tract. These infections usually do not require hospitalization. Actually, only a few lupus patients need to be hospitalized for their infections (Mills, 1994).
What are the different subsets of SLE?
Discoid lupus is an illness characterized by a non-photosensitive, chronic and potentially scarring skin disease. This illness is usually unaccompanied by antinuclear antibodies (ANA) or other autoantibodies. Perhaps 10% of patients with discoid lupus will develop the systemic illness (Mills, 1994).
Drug-induced lupus is usually characterized by fever, hematological abnormalities such as an autoimmune hemolytic anemia or autoimmune thrombocytopenia, or serositis. Skin, renal and neurologic manifestations are uncommon.
Neonatal or congenital lupus occurs when the transplacental acquisition of autoantibodies, specifically anti-Ro (SS-A), a 60-kD ribonucleoprotein, produces in the neonate a transient photosensitive rash, confential complete heart block, thrombocytopenia or hepatobiliary dysfunction (Mills, 1994).
ANA negative or Ro lupus is defined by the absence of an ANA and the present of a lupus-like illness. This disorder is often induced by a partially photosensitive skin rash referred to as subacute cutaneous lupus erythematosus. These patients often demonstrate anti-Ro antibodies, and these patients may be ANA negative (Hahn, 1987).
Figure 2: This is an example of a rash on the back of an individual with subacute cutaneous lupus erythematosus. Permission is pending from the author and will be removed from the site if permission is not granted. Click here to go to the website that contains this picture.
SLE is an autoimmune disease characterized by an elevated serum concentration of immunoglobulin G (IgG) antibodies directed towards self cellular nuclear elements. Small immune complexes that are not cleared by splenic and hepatic complement and Fc receptors tend to become trapped in blood vesels of the kidney and joints, leading to the inflammation that results from the disease. These immune complexes can also lead to the production of proinflammatory cytokines that elicit a variety of physiological responses (Kelley, 1997).
For example, when mice are treated with a human anti-DNA monoclonal antibody, the result is an elevation in both interleukin-1 and TNF-a. These findings, in addition to the fact that high doses of glucocorticoids suppress the synthesis of IL-1 and often pacify many of the symptoms of SLE, is consistent with the hypothesis of a prominent role for inflammatory cytokines in the pathogenenesis of this desease (Segal, 1995). These cytokines synergize in many ways, including their ability to cause symptoms associated with lupus. For example, pain may be caused in joints due to the destructive effects of IL-1 and TNF-a (Kelley, 1997).
What are the effects of lupus?
Ninety percent of patients with SLE experience fatigue. A less common, but more serious, constitutional feature of SLE is persistent fever and weight loss (Mills, 1994). Eighty percent of patients with SLE will present with involvement of the skin or joints. Common symptoms include a photosensitive rash and arthritis. Patients may also experience a fever accompanied by a single organ involvement, such as inflammatory serositis, glomerulonephritis, neuropsychiatric disturbance or hematological disorder (autoimmune hemolytic anemia or thrombocytopenia). Severe, generalized lupus involving multi-organ involvement rarely occurs (Hahn, 1987).
Ninety percent of patients with SLE have musculoskeletal symptoms. Arthralgia is a typical clinical manifestation in SLE patients.The joints most commonly involved are the proximal interphalangeal, metacarpophalangeal, wrist, and knees (Hahn, 1987).
When arthritis occurs in SLE, it is usually the consequence of periarticular inflammation, involving the tendons, which can lead to Jaccouds arthropathy. This is different than rheumatoid arthritis, where lupus is rarely accompanied by frank articular erosions. With inflammatory muscle disease, there is usually an elevation of the muscle enzymes, such as creatine phosphokinase, lactate dehydrogenase or aldolase (Hahn, 1987).
Mucosal ulcers occurs in 30% of patients with SLE. They most often occur on the hard or soft palate or on the nasal septum. The ulcers are usually painless unless there is a secondary infection, such as oral candidiasis. It is controversial whether the ulcers represent a simple inflammatory mucositis or a frank vasculitis of the mucous membranes (McKhann, 1994).
SLE must be distinguished from discoid lupus erythematosus (DLE) which affects the skin (but only in sun exposed regions) and is unlikely to be associated with systemic illness, such as renal disease. A biopsy of sun exposed skin that is not involved with a rash will demonstrate immune complex deposition with SLE, but not with DLE.
Eighty percent of patients with SLE have dermatological manifestations during the course of their illness. The acute cutaneous flare-up causes a photosensitive rash, which often has a butterfly appearance, because the rash involves the bridge of the nose and malar areas of the face. Photosensitivity is less common in patients of color but occurs in 50% of all patients with SLE. The rash of subacute cutaneous lupus is observed in anti-Ro positive patients. This eruption is intermediately photosensitive and can either have an annular, polycyclic appearance (Kotzin, 1986).
Twenty-five percent of patients with SLE have discoid skin lesions. These lesions are often on the face or the inner pinna of the ear, but the lesions are not photosensitive. These lesions are characterized clinically by follicular plugging, skin atrophy, and scaling (Kotzin, 1986).
Alopecia occurs in 50% of patients. Typically this is manifest as reversible hair thinning during periods of disease activity,demonstrated by the ease with which hair can be plucked from the scalp. Discoid lesions involving the scalp leads to scarring alopecia (Kotzin, 1986).
Figure 3: A severe inflammatory skin reaction in the upper dermis of a patient with SLE in which the basal layer is undergoing
vacuolization and dissolution, and there is purpura with RBC's in the upper dermis (which are the reason for the rash). Click here to go to the website that has this picture. Permission to use this picture is pending from the author of the website and will be removed if permission is not granted.
Anemia of chronic inflammation is a common feature of aggravated SLE. Coombs positive hemolytic anemia with an acute declining hematocrit and reticulocytosis is a characteristic of SLE, but only appears in 10% of patients (Hahn, 1987).
Autoimmune thrombocytopenia purpura can be a presenting feature of SLE or occur at any time in the course of the illness. Thrombocytopenia as a consequence of the antiphopholipid antibody syndrome has also been described in SLE. Leukopenia with lymphopenia is also a characteristic feature of SLE (Hahn, 1987).
Kidney disease occurs in about 50% of patients--the consequence of the deposition of immune complexes containing anti-DNA in the kidney. Serum antibodies to anti-DNA are a marker for the development of renal disease (Mills, 1994).
Figure 4: This is a picture of the thickened capillary walls in the patient with lupus nephritis. This is what leads to renal failure in those individuals with the disease. Permission to use this picture is pending and it will be removed if permission is not granted. Click here to go to the website that has this picture.
Effects on the Central Nervous System
Neuropsychiatric complications occur in 50% of SLE patients and include acute and chronic, and localized and diffuse manifestations. Twenty-five percent of patients with lupus experience seizures. Diffuse cerebral dysfunction can result in organic effective disorder, personality disorder, psychosis, or coma. Vascular or migraine headaches occur in 10% of lupus patients. Recurrent involvement of the central nervous system may result in an organic brain syndrome and dementia (Bluestein, 1992).
Active SLE can be accompanied by coronary artery vasculitis and, on rare occasion, this has produced myocardial infarction. There is an increased incidence of atherosclerotic heart disease in SLE, including in premenopausal women. This may be related to coronary artery pathology initiated by immune complex deposition. SLE patients with the secondary antiphospholipid antibody syndrome also develop myocardial infractions but on the basis of bland coronary artery thrombosis (Briley et al., 1989).
Nonspecific inflammatory liver disease has been described in lupus. Progression to cirrhosis as a consequence of inflammatory liver disease in SLE is rare.
Secondary Antiphospholipid Antibody Syndrome
What are antiphospholipid antibodies and what is their role in patients with lupus?
The term antiphospholipid antibodies is used for antibodies responsible for the lupus anticoagulant test, as well as those detected in the anticardiolipin ELISA (Harris, 1985). Antiphospholipid antibodies (aPL) are part of a group of antibodies that are associated with problems relating to abnormal blood clotting such as miscarriages, deep vein thromboses, pulmonary emboli, and strokes. They may also be related to the presence of migraine headaches and low platelet counts (thrombocytopenia). They can be found in the blood of some people with lupus and other autoimmune diseases and occasionally in people without any other known disease. A variety of blood tests are used to detect the presence of these antibodies.
Patients with SLE have an increased incidence of the antiphospholipid antibody syndrome. This syndrome is defined by the co-occurrence of thrombotic events and the presence of autoantibodies against negatively charged phospholipid, such as a lupus anticoagulant, or anti-cardiolipin antibody (Alarcón-Segovia et al., 1989). This syndrome occurs most frequently in patients with high titer IgG anti-cardiolipin antibodies or lupus anticoagulant. Patients with this disorders are at risk for recurrent arterial and venous thrombosis, thrombocytopenia, and fetal wastage. The mechanisms of this prothrombotic diathesis are uncertain, but these autoantibodies bind to target antigens on endothelial cells, platelets or coagulation factors producing a hypercoaguable state (Asherson et al., 1989).
Is Lupus Inherited?
A question frequently posed by expectant mothers out of concern for themselves and their future newborns, the answer, however, is not yet clear. It is true that the inheritance of genes from our parents is important in the development of lupus, but the answer is much more complicated than a simple yes. Research related to lupus suggests that genetics does play an important role in determining those individuals that will be affected by the disease. It is estimated that four to six or more genes must be combined for a person to inherit a susceptibility to acquire lupus (Mills, 1994). Therefore, it is nearly impossible to inherit all the genes necessary to develop lupus from a single parent and this is one reason why it is unusual for lupus to occur in multiple generations of a family. If only some of the lupus genes are inherited, a person may test positive for some of the immunological tests, such as the antinuclear antibody (ANA) test, but may not actually have lupus. A positive ANA occurs in up to one third of healthy family members of lupus patients (Mills, 1994).
Important genetic information in SLE is located on the short arm of chromosome #6. The genes on chromosome #6 have many complex functions. Some regulate complement components, which, when missing, a milder form of lupus, which usually lacks kidney involvement, may develop. Complement genes are important but they are not the whole story in the development of this form of lupus. For example, many susceptible individuals who lack these genes for complement never develop lupus at all (Mills, 1994).
Another important area on the short arm of chromosome #6 is the human leukocyte antigen (HLA) region. It is located next to the area for complement genes. The HLA area has been very thoroughly studied since it is used to match donors genetically to recipients for organ transplants. it is further divided into smaller regions called HLA-A, HLA-B, HLA-C, HLA-DR, HLA-DQ. In lupus patients there is an increased frequency of the HLA genes called Al, B8, Dr2, or Dr-3 and DQ1. Associations between genes and diseases such as lupus are established by comparing lupus patients to a normal or control population. Particular HLA markers found in white lupus patients (on whom the majority of studies have focused) have not been shown to be present in black patients or Japanese patients with lupus. The reasons for these differences are not clear. There may be other as yet unknown genes or there may also be important genes on other chromosomes, which play a part in making a person susceptible to developing lupus (McKhann, 1994).
The newest research methods now being used to study genetics come from the field of molecular biology. They are redefining the way in which we look at the genetics of disease. When methods of molecular biology are used to study the HLA system in various diseases, we are finding that what looked like a specific HLA type, by our current standard tests, in reality is slightly different and Much more complex. This methodology should lead to new important findings, both in genetics and in lupus. Another way of studying the genetics of lupus is by looking at families in which lupus occurs in more than one member. Familial cases are reported in approximately 10% of the lupus population (McKhann, 1994). The most thoroughly studied family association is between twins. If one of a pair of identical twins has lupus, the other will develop it more than two thirds (69%) of the time. If a fraternal or non-identical twin has lupus, the other twin has only a 5% chance of developing it. It is obvious that genetics are important, since the frequency of developing lupus is so much higher in identical twins than in fraternal twins when one of the twins already has lupus. Genetic factors cannot be the only answers, however, or susceptible identical twins would both develop lupus 100% of the time. Environmental factors, therefore, must also be important. It appears that some people are genetically predisposed to develop lupus but then must be exposed to the proper environmental triggers in order to have the disease (McKhann, 1994).
In conclusion, heredity is involved in the development of lupus but it is rare to have more than one family member who has lupus. Much is known about the genetics of lupus, yet even more needs to be discovered. It is only through careful family studies using molecular biological techniques that the answer to the genetic dilemma of SLE and the relationship between heredity and environment will be solved.
What treatments/possible cures are available?
Immunosuppressive drugs used in treatment of SLE include azathioprine (Imuran), alkylating agents (nitrogen mustard, cyclophosphamide, and chlorambucil). Methotrexate is beneficial especially in the setting of multi-joint inflammation.
The risk of certain types of infection can be decreased with immunization (vaccinations). Passive immunization (vaccinating the patient with a killed virus) poses no problems in lupus patients. Gammaglobulin is an example of a vaccine, which uses a nonspecific antibody instead of a live virus. Immunization with vaccines that use live viruses will result in a lupus flare. However, polio, measles, and tetanus vaccines, which all use live viruses, have been given to hundreds of thousands of lupus patients with no adverse reactions (McKhann, 1994).
Lupus patients may have adverse reactions to allergy shots (immunotherapy). These people will experience a lupus flare following this treatment. For this reason, in 1989, the World Health Organization recommended that patients with autoimmune diseases should not receive certain types of allergy shots. Allergy shots could potentially cause the patient to make more anti-DNA and other lupus-related antibodies in addition to making antibodies against the agent causing the allergy (Mills, 1994). Some lupus patients may also experience difficulties after receiving tetanus or flu vaccines. Antibody levels against the flu virus achieve only half the desired level for half as long in those with lupus. About 20% of patients with lupus may feel sick or achy for a few days following a flu vaccination, where only 10% of non-lupus patients will suffer such adverse effects following a flu shot (McKhann, 1994).
Drugs such as procainamide or hydralazine can induce the production of antinuclear antibodies, especially anti-histone antibodies, and occasionally a SLE-like illness (Hahn, 1987).
Fever, joint pain, arthritis, and serositis can often be managed effectively by non-steroidal anti-inflammatory drugs (NSAIDs) alone. NSAIDs are usually well-tolerated, but they are associated with a range of potential side effects or toxicities, such as gastrointestinal problems and peptic ulcers (Kotzin, 1986).
Anti-malarial drugs (hydroxycholoroquine, chloroquine, and quinacrine) are most effective for the management of cutaneous features of lupus. These drugs are among the safest oral medications available for treatment (McKhann, 1994).
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