Systemic lupus erythematosus (SLE), also often simply called lupus, is a disease that primarily affects young women. It is an uncommon disease that occurs in approximately one in 2000 individuals, but the frequency of the disease varies in different racial and ethnic groups. For example, lupus occurs more frequently in African Americans and Hispanics than in Caucasians. Nevertheless, SLE occurs with sufficient frequency that doctors often consider the diagnosis in their evaluation of patients who have systemic symptoms that may be compatible with lupus and many people have heard of the disease or know someone who has it. The peak incidence of SLE occurs between the ages of 15 and 40 and is five to nine times more common in women than men, though it can also occur in children and older adults. In these two age extremes the incidence is more similar between females and males.
Lupus is an autoimmune disease, which means that the symptoms and damage caused by the disease are a result of abnormal activation of the body’s immune system. It can be difficult to diagnose because many symptoms of the disease - such as fatigue - occur in many other conditions. In addition, SLE can affect many parts of the body, such as the skin, the blood vessels, the kidney, and the joints. However, not all of these areas are affected in all patients with lupus. A specialist in autoimmune disease, usually a rheumatologist, generally does the diagnosis and treatment of SLE.
For the purposes of this overview, lupus and SLE are used interchangeably. However, the term “lupus” is applied to several diseases.
SLE is a systemic disease that affects the entire body.
Discoid Lupus Erythematosus refers to a particular skin lesion that usually begins as a red bump and progresses to look like a scar, often with loss of skin color in the lesion. Discoid lupus may occur as an isolated skin disease without any manifestations of SLE, or it may occur as part of SLE.
Neonatal Lupus is a form of disease that occurs in newborn children of mothers who have lupus as a result of transfer of antibodies from mother to fetus. Although the symptoms of neonatal lupus may be severe, such as complete heart block, they generally are self-limited and disappear after the mother’s antibodies are cleared from the baby’s system.
Drug-induced Lupus (DIL) is an infrequently encountered condition that occurs when lupus-like symptoms develop as a result of exposure to certain medications. The most common symptoms are fatigue, fever, joint pain (arthralgias) and muscle pain (myalgias). Many different classes of medications can cause DIL, but the most common drugs are procainamide, hydralazine, and isoniazid.
Diagnosis of Lupus
There is no single test or procedure that can unequivocally diagnose lupus. The diagnosis requires the presence of one or more abnormal blood tests and a group of compatible symptoms and clinical signs of the disease.
The most common abnormality in the blood is the presence of anti-nuclear antibodies (ANA). While it is extremely rare for a person to have SLE and not have a positive ANA test, many other conditions can cause a positive ANA. In fact, it is not uncommon for women in particular to have a positive ANA test without having any symptoms of disease. Thus, the presence of an ANA does not prove that a person has lupus.
The ANA is an example of an autoantibody. Antibodies are produced by the immune system in response to foreign proteins (antigens) of infecting organisms (for example, bacteria) to facilitate destruction of the organism. However, an autoantibody is an antibody that is produced in response to a person’s own proteins (autoantigens) and can cause damage to tissues because of inappropriate activation of the immune system. The production of autoantibodies is a hallmark of SLE. Other autoantibodies that are characteristic, but less frequently present in lupus are the anti-dsDNA, anti-Sm, anti-SSA, anti-SSB, and anti-phospholipid antibodies. The presence of these autoantibodies in the blood may also indicate the presence of SLE. Lupus causes characteristic pathology in several tissues. In some cases, biopsy of involved tissue, such as the skin or the kidney, may help establish the diagnosis. Diagnosis of particular manifestations of lupus is accomplished by specific laboratory testing or imaging studies. For example, brain MRI can be helpful in diagnosing lupus involvement of the central nervous system.
Symptoms of Lupus
Different people with lupus will experience different symptoms and these symptoms often vary with time. Common symptoms include extreme fatigue, joint pain and swelling, muscle pain, unexplained fever, and skin rash. Although several kinds of rash may develop on different parts of the body, a very characteristic facial rash called a “malar” or “butterfly” rash frequently occurs on the cheeks and across the nose. This rash is a photosensitive rash, which means that it develops and worsens as a result of sun exposure. People with lupus sometimes also feel more ill after significant sun exposure. Other symptoms of SLE may include headache, cold finger tips that turn pale and blue or purple, chest pain, excessive hair loss, and swollen glands. Another characteristic feature of SLE is the occurrence of “flares” of disease. During a flare symptoms worsen, or additional symptoms develop and then resolve when the flare has been treated. New symptoms of disease may also appear months or years after the diagnosis of SLE has been made.
Clinical Features of Lupus
The severity of SLE ranges from relatively mild disease that only partially impacts a person’s ability to lead a normal life to severe disease that can cause permanent damage to one or more organ – and even death. Some of the more common organ systems involved by lupus include the joints, kidneys, and the blood vessels. The particular clinical features that a person with SLE experiences depends upon the organ systems involved. Some examples are described below.
• Kidneys: SLE causes inflammation of the kidneys called nephritis. In the early stages of lupus nephritis, a person will experience no symptoms and the presence of inflammation in the kidney is only detected by a urinalysis by a physician. However, left untreated, lupus nephritis can progress to kidney failure resulting in severe life-threatening illness. The fact that kidney disease can progress with little or no symptoms emphasizes the importance of regular medical follow-up once lupus is diagnosed.
• Blood: Patients with SLE commonly have reduced numbers of blood cells; the reduction in red bloods cells results in anemia, while the reduction in white blood cells may increase the risk of infection. Lupus patients also frequently have reduced numbers of platelets. These blood deficiencies most commonly are the result of autoantibodies, for example anti-platelet antibodies that cause premature removal of platelets. Another group of antibodies that may cause significant problems in the blood are the anti-phospholipid antibodies. These antibodies bind to specific molecules in cell membranes that are involved in blood clotting and can cause the blood to clot abnormally. Abnormal blood coagulation in the presence of these anti-phospholipid antibodies is called the Antiphospholipid Syndrome, or APLS. APLS commonly occurs in SLE, but can also occur as a single, distinct condition. In either case, the syndrome can cause many serious conditions, including blood clots in the legs or arms, stroke or heart attack, and miscarriage.
• Heart: SLE can cause inflammation of the pericardium that surrounds the heart resulting in chest pain. The heart muscle itself may also become inflamed (myocarditis). Lupus also may cause inflammation of the coronary blood vessels resulting in heart attack. Blood clots resulting from APLS can develop on the heart valves resulting in dysfunction of the valve and small pieces of clot breaking loose to block small arteries in other organs, such as the brain. Apart from direct involvement of the heart, it is also clear that people with SLE have more rapid progression of atherosclerosis (hardening of the arteries) than the general population. Thus it is particularly important for SLE patients to try to minimize any and all of their other cardiovascular risk factors.
• Lungs: SLE can involve the lungs in several ways. The lining of the lungs can become inflamed (pleurisy) resulting in chest pain, particularly with deep breathing. The lungs themselves may become inflamed, which causes shortness of breath and reduced exercise tolerance and, over time, can cause permanent scarring of the lung. SLE can also affect the blood vessels in the lung, causing pulmonary hypertension. Severe cases of SLE may result in bleeding into the lung.
• Central Nervous System: Lupus can have a variety of effects on the nervous system. Symptoms can include headache, visual disturbances, problems with memory and cognition, seizures or stroke, and many others. Collectively, involvement of the brain and central nervous system in SLE is called neuropsychiatric lupus. This can be an especially difficult manifestation of SLE to diagnose and treat – not only because many of the symptoms are nonspecific, but also because other processes, such as depression and chronic pain, can affect brain function. Detailed neuropsychiatric testing can be very helpful in diagnosing some of the more subtle manifestations of neuropsychiatric lupus.
• Lupus and Pregnancy: Pregnancy carries special risk in SLE because there is significantly increased risk of flare of disease activity during pregnancy. Lupus also results in a significantly increased risk of miscarriage. Pregnancy in lupus is therefore considered high risk and it is critical that an obstetrician and the rheumatologist carefully coordinate the care of the pregnant woman with lupus and help her weigh the risks and benefits of treatment during pregnancy. Because the high estrogen state of pregnancy increases lupus activity, there was longstanding concern that oral contraceptives might also increase the risk of a disease flare in SLE. However, a recent large randomized trial has clearly shown that oral contraceptives do not increase the risk of flare among women with SLE whose disease is stable.
The Cause of Lupus
The cause of lupus is unknown. It is clear that there is an important genetic component of the disease because SLE can run in families and there is an increased frequency of the disease in twins compared to the general population. Genetic association studies have implicated several genes in the pathogenesis of lupus. Although no single agent has been shown to cause the disease, it is likely that several kinds of infection or environmental exposure can trigger the disease in susceptible individuals. Much progress has been made in defining specific abnormalities of immune function in patients with this disease..
The current general view of the origin and development (pathogenesis) of lupus is that abnormal exposure to autoantigens, resulting from abnormal processing or removal of these antigens, results in inappropriate activation of the innate immune system. This activation in particular leads to increased production of an immune signaling molecule called interferon alpha, which in turn activates an array of immune response genes leading to widespread activation of the adaptive immune system. Additional intrinsic genetic predispositions – or extrinsic factors such as hormones or environmental agents – affect the ultimate intensity or pattern of disease expression. Recent advances in identifying key elements in the pathogenesis of SLE have provided much opportunity for developing new specialized treatments for the disease. In addition to research supported by the National Institutes of Health, several private organizations are actively supporting targeted research in the cause and treatment of lupus, including the Alliance for Lupus Research (www.lupusresearch.org) and the Lupus Research Institute (www.lupusresearchinstitute.org).
Treatment of Lupus
Treatment of most forms of SLE involves suppression of the immune system, as summarized in Table I. The most commonly used immunosuppressive drugs for moderately severe lupus are the corticosteroids, such as prednisone. These agents effectively suppress disease activity for most patients, but they also have many undesirable side effects. Doctors therefore generally try to minimize the use of corticosteroids whenever possible.
The chloroquine drugs (hydroxychloroquine, chloroquine and quinacrine) are very important medications for the treatment of lupus. They work to modulate the activity of the immune system and can reduce the frequency of disease flares. The chloroquines are generally well tolerated, but occasionally can cause pigmentation of the retina. It is therefore important to have regular eye exams when taking one of these medications.
Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen can be effective for the joint and muscle pain experienced by lupus patients.
More severe manifestations of SLE, such as kidney disease, require more intensive suppression of the immune system. Several immunosuppressive medications are used for lupus. One of the most potent is cyclophosphamide, which is reserved for the most severe organ-threatening or life-threatening disease because of its own severe side effects. One of the most important recent advances in the treatment of lupus has been the use of mycophenolate mofetil (CellCept) for the treatment of lupus nephritis. This drug has many fewer side effects than cyclophosphamide, is generally well tolerated, and is very effective for many cases of lupus nephritis and other forms of the disease. Lupus patients who have ALPS require chronic anticoagulation with warfarin (Coumadin). In fact, as outline in the table, there are a number of medications that are used to treat lupus, which provide significant symptoms relief for a majority of patients. With the exception of warfarin, which inhibits blood clotting, these agents affect the function of the immune system by suppressing the function of immune cells, modulating the production of immune cell products ("immunomodulatory"), destroying immune cells (cytotoxic"), or by altering the effects of estrogen on the immune system ("hormonal"). In addition, a number of new treatments for SLE that target specific components of the immune system are also currently under development. As is the case with all medications, these drugs can have significant side effects. Because lupus is a chronic disease, some medication generally must also be taken regularly for long periods of time. It is therefore also frequently necessary to monitor for medication side effects with regular blood tests.
SLE Treatment Options
- Immunosuppressive : corticosteroids; azathioprine; cyclosporin; methotrexate; rituximab (investigational)
- Immunomodulatory: chloroquines; mycophenolate; mofetil
- Anti-inflammatory: Non-steroidal anti-inflammatory drugs (eg. ibuprofen)
- Cytotoxic: Cyclophosphamide; chlorambucil
- Hormonal: DHEA
- Anticoagulant: warfarine
Living with Lupus
Once a person has developed SLE, it is generally a chronic condition and many people with lupus need to take medication for many years. However, with one of more of these medications, most people are also able to achieve good control of their disease. Despite the many symptoms of the disease and the potential for side effects from medication, most people with lupus can expect to maintain a high quality of life and have a normal life expectancy. A key aspect of maintaining this quality is to be proactive in managing the disease. Preventing disease flares is more effective than trying to treat a flare once it has developed. Therefore, keeping a regular medication schedule is critical, as is avoiding sun exposure by wearing wide brimmed hats and regular use of SPF30 or greater sunscreen on all exposed skin. Adequate rest and limiting stress is also very important. In addition, recognizing the signs of a flare and taking steps early to minimize the severity of the flare in communication with the doctor can be very helpful.
A support structure from friends and family can also be very helpful. A common experience of lupus patients is that they feel a lack of empathy from people around them because while they may feel significant pain and illness, there are generally few outward appearances of disease. Educating friends and family about the manifestations of lupus can be very effective in this regard. Patient oriented organizations such as the Lupus Foundation of America (www.lupus.org), many state lupus organizations, such as the Lupus Foundation of Northern California (www.balf.org) and the Arthritis Foundation, which provides support for people with all kinds of arthritis including that caused by lupus, (www.arthritis.org) are valuable sources of such support.
References
Rahman A, Isenberg DA, Mechanisms of Disease: Systemic Lupus Erythematosus, New England Journal of Medicine, 2008, 358:929-939.
Schur PH, Bernas BL, Pregnancy in Women with Systemic Lupus Erythematosus, UpToDate Patient Information, http://patients.uptodate.com/topic.asp?file=lupus/7111
Petri M, Kim MY, Kalunian K, et al., Combined Oral Contraceptives in Women with Systemic Lupus Erythematosus, New England Journal of Medicine, 2005, 353:2550-2558.
Von Feldt, JM, Atherosclerosis and central nervous system involvement in systemic lupus erythematosus, J Clin Rheumatology 2007, 13:179-80.
Izmirly PM, Rivera TL, Buyon JP. Neonatal lupus syndromes, Rheum Dis Clin North Am, 2007, 33:267-85.
Crow, MK, Type I interferon in systemic lupus erythematosus, Curr Top Microbiol Immunol. 2007, 316:359-86
David I. Daikh, M.D., Ph.D.
Associate Professor of Medicine
University of California, San Francisco
Chief, Rheumatology Section
San Francisco VA Medical Center
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