Definition
Lupus is a chronic autoimmune disease in which the body’s immune system becomes hyperactive and attacks normal, healthy tissue. This results in symptoms such as inflammation, swelling, and damage to joints, skin, kidneys, blood, the heart, and lungs.
Under normal function, the immune system makes proteins called antibodies in order to protect and fight against antigens such as viruses and bacteria.
It makes the immune system unable to differentiate between antigens (a substance capable of inducing a specific immune response) and healthy tissue. This leads the immune system to direct antibodies against the healthy tissue – not just antigens – causing swelling, pain, and tissue damage.
History
The history can be divided into three periods: classical, neoclassical, and modern. This article concentrates on developments in the present century which have greatly expanded our knowledge about the pathophysiology, clinical-laboratory features, and treatment of this disorder.
Classical period (1230-1856)
The history of lupus during the classical period was reviewed by Smith and Cyr in 1988. Of note are the derivation of the term lupus and the clinical descriptions of the cutaneous lesions of lupus vulgaris, lupus profundus, discoid lupus, and the photosensitive nature of the malar or butterfly rash.
The word ‘lupus’ (Latin for ‘wolf’) is attributed to the thirteenth century physician Rogerius who used it to describe erosive facial lesions that were reminiscent of a wolf’s bite. Classical descriptions of the various dermatologic features of lupus were made by Thomas Bateman, a student of the British dermatologist Robert William, in the early nineteenth century; Cazenave, a student of the French dermatologist Laurent Biett, in the mid-nineteenth century; and Moriz Kaposi (born Moriz Kohn), student and son-in-law of the Austrian dermatologist Ferdinand von Hebra, in the late nineteenth century.
The lesions now referred to as discoid lupus were described in 1833 by Cazenave under the term “erythema centrifugum,” while the butterfly distribution of the facial rash was noted by von Hebra in 1846. The first published illustrations of lupus erythematosus were included in von Hebra’s text, Atlas of Skin Diseases, published in 1856.
Neoclassical period (1872- 1948)
The Neoclassical era of the history of lupus began in 1872 when Kaposi first described the systemic nature of the disorder: “…experience has shown that lupus erythematosus … may be attended by altogether more severe pathological changes, and even dangerous constitutional symptoms may be intimately associated with the process in question, and that death may result from conditions which must be considered to arise from the local malady.”
Kaposi proposed that there were two types of lupus erythematosus; the discoid form and a disseminated (systemic) form. Furthermore, he enumerated various signs and symptoms which characterized the systemic form, including:
- subcutaneous nodules
- arthritis with synovial hypertrophy of both small and large joints
- lymphadenopathy
- fever
- weight loss
- anemia
- central nervous system involvement
The existence of a systemic form was firmly established in 1904 by the work of Osler in Baltimore and Jadassohn in Vienna. Over the next thirty years, pathologic studies documented the existence of nonbacterial verrucous endocarditis (Libman-Sacks disease) and wire-loop lesions in individuals with glomerulonephritis; such observations at the autopsy table led to the construct of collagen disease proposed by Kemperer and colleagues in 1941. This terminology, ‘collagen vascular disease,’ persists in usage more than seventy years after its introduction.
Modern era (1948-present)
The sentinel event which heralded the modern era was the discovery of the LE cell by Hargraves and colleagues in 1948. The investigators observed these cells in the bone marrow of individuals with acute disseminated lupus erythematosus and postulated that the cell “…is the result of…phagocytosis of free nuclear material with a resulting round vacuole containing this partially digested and lysed nuclear material…”.
This discovery ushered in the present era of the application of immunology to the study of lupus erythematosus; it also allowed the diagnosis of individuals with much milder forms of the disease. This possibility, coupled with the discovery of cortisone as a treatment, changed the natural history of lupus as it was known prior to that time.
Two other immunologic markers were recognized in the 1950s as being associated with lupus: the biologic false-positive test for syphilis and the immunofluorescent test for antinuclear antibodies. Moore, working in Baltimore, demonstrated that systemic form of this disease developed in 7 percent of 148 individuals with chronic false-positive tests for syphilis and that a further 30 percent had symptoms consistent with collagen disease.
Friou applied the technique of indirect immunofluorescence to demonstrate the presence of antinuclear antibodies in the blood of individuals with systemic lupus. Subsequently, there was the recognition of antibodies to deoxyribonucleic acid (DNA) and the description of antibodies to extractable nuclear antigens (nuclear ribonucleoprotein [nRNP], Sm, Ro, La), and anticardiolipin antibodies; these autoantibodies are useful in describing clinical subsets and understanding the etiopathogenesis of lupus.
The Lupus Erythematosus cell is discovered.
This discovery ushered in the present era of the application of immunology to the study of lupus erythematosus; it also allowed the diagnosis of individuals with much milder forms of the disease. This possibility, coupled with the discovery of cortisone as a treatment, changed the natural history of lupus as it was known prior to that time.
Two other immunologic markers were recognized in the 1950s as being associated with lupus: the biologic false-positive test for syphilis and the immunofluorescent test for antinuclear antibodies. Moore, working in Baltimore, demonstrated that systemic lupus developed in 7 percent of 148 individuals with chronic false-positive tests for syphilis and that a further 30 percent had symptoms consistent with collagen disease.
Friou applied the technique of indirect immunofluorescence to demonstrate the presence of antinuclear antibodies in the blood of individuals with systemic lupus. Subsequently, there was the recognition of antibodies to deoxyribonucleic acid (DNA) and the description of antibodies to extractable nuclear antigens (nuclear ribonucleoprotein [nRNP], Sm, Ro, La), and anticardiolipin antibodies; these autoantibodies are useful in describing clinical subsets and understanding the etiopathogenesis of lupus.
Genetic component recognized
The familial occurrence of systemic lupus was first noted by Leonhardt in 1954 and later studies by Arnett and Shulman at Johns Hopkins. Subsequently, familial aggregation of lupus, the concordance of lupus in monozygotic twin pairs, and the association of genetic markers with lupus have been described over the past twenty years.
Molecular biology techniques have been applied to the study of human lymphocyte antigen (HLA) Class II genes to determine specific amino acid sequences in these cell surface molecules that are involved in antigen presentation to T-helper cells in individuals with lupus. These studies have resulted in the identification of genetic-serologic subsets of systemic lupus that complement the clinico-serologic subsets noted earlier.
It is hoped by investigators working in this field that these studies will lead to the identification of etiologic factors (e.g., viral antigens/proteins) in lupus.
Over the last decade or so, we have witnessed significant advances in the understanding of the genetic basis of lupus, and of the immunological derangements which lead to the clinical manifestations of the disease.
Advances have been made in the assessment of the impact of the disease in general, and in minority population groups, in particular and efforts are being made towards defining lupus biomarkers which may help both to predict disease outcome and to guide treatments.
Prevalence and incidence
Lupus appears to be a relatively uncommon disease. The prevalence has been estimated in several different countries mostly, however, in the developed world, using different techniques of case ascertainment. The authors of one metaanalysis (including those studies in Europe and North America) suggested an overall weighted mean prevalence of 24/100,000 population.Three English studies have produced prevalence estimates of: 12/100,000, 25/100,000 and 28/100,000 and the only study in N Ireland estimated a rate of 254/100,000. Studies in countries which include predominantly white populations have resulted in lower prevalence estimates (e.g. England) when compared with studies among populations with a significant proportion of Afro-Caribbeans, Asians and Hispanics.
It is more difficult to estimate incidence for a rare disease but studies in both North America and Europe have produced estimates that are similar (approximately 1 – 8 cases per 100,000 persons per year).The lowest rates of incidence were seen among Caucasian Americans, Canadians and Spaniards and the highest rates among Asian (10.0 cases /100,000) and Afro-Caribbean (21.9 cases /100,000) residents of the UK. In an average UK practice list of 3000 patients, therefore, a GP would not expect to see a new case of lupus more often than every 7-10 years.
Types
There are three main types of lupus:
Systemic lupus erythematosus (eh-RITH-eh-muh-TOE-sus) is the most common form. It’s sometimes called SLE, or just lupus. The word “systemic” means that the disease can involve many parts of the body such as the heart, lungs, kidneys, and brain. SLE symptoms can be mild or serious.
Systemic lupus
Discoid lupus erythematosus mainly affects the skin. A red rash may appear, or the skin on the face, scalp, or elsewhere may change color.
Discoid lupus
Drug-induced lupus is triggered by a few medicines. It’s like SLE, but symptoms are usually milder. Most of the time, the disease goes away when the medicine is stopped. More men develop drug-induced lupus because the drugs that cause it, hydralazine and procainamide, are used to treat heart conditions that are more common in men.
Risk factors
Risk factors for developing lupus include:
Gender – more than 90% of people with lupus are women. Before puberty, boys and girls are equally likely to develop the condition
Age – symptoms and diagnosis of lupus often occur between the ages of 15-45. Around 15% of people who are later diagnosed with lupus, experienced symptoms before the age of 18
Race – in the US, lupus is more common, more severe and develops earlier in African-Americans, Hispanics/Latinos, Asian-Americans, Native Americans, Native Hawaiians and Pacific Islanders than in the white population
Family history – first-degree or second-degree relatives of a person with lupus have a 4-8% risk of developing lupus. One study suggests that sisters of lupus patients have as high as a 10% chance of developing lupus. In another 10-year prospective study, researchers observed a 7% incidence of lupus in first-degree relatives of lupus patients.
Causes of Lupus
Many (but not all) scientists believe that lupus develops in response to a combination of factors both inside and outside the body, including hormones, genetics, and environment.
Hormones
Hormones are the body’s messengers. They regulate many of the body’s functions. Because nine of every 10 occurrences of lupus are in females, researchers have looked at the relationship between estrogen and lupus.
While men and women both produce estrogen, its production is much greater in females. Many women have more symptoms before menstrual periods and/or during pregnancy when estrogen production is high. This may indicate that estrogen somehow regulates the severity of this disease. However, no causal effect has been proven between estrogen, or any other hormone, and lupus. And, studies of women with lupus taking estrogen in either birth control pills or as postmenopausal therapy have shown no increase in significant disease activity. Researchers are now focusing on differences between men and women, beyond hormone levels, which may account for why women are more prone to lupus and other autoimmune diseases.
Genetics
Researchers have now identified more than 50 genes which they associate with lupus. These genes are more commonly seen in people with lupus than in those without the disease, and while most of these genes have not been shown to directly cause lupus, they are believed to contribute to it.
In most cases, genes are not enough. This is especially evident with twins who are raised in the same environment and have the same inherited features yet only one develops lupus. Although, when one of two identical twins has infected, there is an increased chance that the other twin will also develop the disease (30% percent chance for identical twins; 5-10% percent chance for fraternal twins).
Lupus can develop in people with no family history of it, but there are likely to be other autoimmune diseases in some family members.
Certain ethnic groups (people of African, Asian, Hispanic/Latino, Native American, Native Hawaiian, or Pacific Island descent) have a greater risk of developing it, which may be related to genes they have in common.
Environment
Most researchers today think that an environmental agent, such as a virus or possibly a chemical, randomly encountered by a genetically susceptible individual, acts to trigger the disease. Researchers have not identified a specific environmental agent as yet but the hypothesis remains likely.
While the environmental elements that can trigger lupus and cause flares aren’t fully known, the most commonly cited are ultraviolet light (UVA and UVB); infections (including the effects of the Epstein-Barr virus), and exposure to silica dust in agricultural or industrial settings.
Symptoms of Lupus
There are many symptoms, and differ from person to person. Some of the more common ones are
- Pain or swelling in joints
- Muscle pain
- Fever with no known cause
- Red rashes, most often on the face (also called the “butterfly rash”)
- Chest pain when taking a deep breath
- Hair loss
- Pale or purple fingers or toes
- Sensitivity to the sun
- Swelling in legs or around eyes
- Mouth ulcers
- Swollen glands
- Feeling very tired
- Symptoms may come and go. When you are having symptoms, it is called a flare. Flares can range from mild to severe. New symptoms may appear at any time.
Diagnosis and test
Diagnosing lupus is difficult because signs and symptoms vary considerably from person to person. Signs and symptoms of lupus may vary over time and overlap with those of many other disorders. No one test can diagnose lupus. The combination of blood and urine tests, signs and symptoms, and physical examination findings leads to the diagnosis.
Laboratory tests
Blood and urine tests may include:
Complete blood count: This test measures the number of red blood cells, white blood cells and platelets as well as the amount of hemoglobin, a protein in red blood cells. Results may indicate you have anemia, which commonly occurs in lupus. A low white blood cell or platelet count may occur in lupus as well.
Erythrocyte sedimentation rate: This blood test determines the rate at which red blood cells settle to the bottom of a tube in an hour. A faster than normal rate may indicate a systemic disease, such as lupus. The sedimentation rate isn’t specific for any one disease. It may be elevated if you have lupus, another inflammatory condition, cancer or an infection.
Kidney and liver assessment: Blood tests can assess how well your kidneys and liver are functioning. It can affect these organs.
Urinalysis. An examination of a sample of your urine may show an increased protein level or red blood cells in the urine, which may occur if this disease has affected your kidneys.
Antinuclear antibody (ANA) test. A positive test for the presence of these antibodies — produced by your immune system — indicates a stimulated immune system. While most people with lupus have a positive ANA test, most people with a positive ANA do not have lupus. If you test positive for ANA, your doctor may advise more-specific antibody testing.
Imaging tests
If your doctor suspects that lupus is affecting your lungs or heart, he or she may suggest:
Chest X-ray. An image of your chest may reveal abnormal shadows that suggest fluid or inflammation in your lungs.
Echocardiogram. This test uses sound waves to produce real-time images of your beating heart. It can check for problems with your valves and other portions of your heart.
Biopsy
It can harm your kidneys in many different ways, and treatments can vary, depending on the type of damage that occurs. In some cases, it’s necessary to test a small sample of kidney tissue to determine what the best treatment might be. The sample can be obtained with a needle or through a small incision.
Treatment and medications
Treatment depends on your signs and symptoms. Determining whether your signs and symptoms should be treated and what medications to use requires a careful discussion of the benefits and risks with your doctor. As your signs and symptoms flare and subside, you and your doctor may find that you’ll need to change medications or dosages. The medications most commonly used to control include:
Nonsteroidal anti-inflammatory drugs (NSAIDs): Over-the-counter NSAIDs, such as naproxen sodium (Aleve) and ibuprofen (Advil, Motrin IB, others), may be used to treat pain, swelling and fever associated with lupus. Stronger NSAIDs are available by prescription. Side effects of NSAIDs include stomach bleeding, kidney problems and an increased risk of heart problems.
Antimalarial drugs: Medications commonly used to treat malaria, such as hydroxychloroquine (Plaquenil), also can help to control. Side effects can include stomach upset and, very rarely, damage to the retina of the eye.
Corticosteroids: Prednisone and other types of corticosteroids can counter the inflammation of lupus but often produce long-term side effects including weight gain, easy bruising, thinning bones (osteoporosis), high blood pressure, diabetes and increased risk of infection. The risk of side effects increases with higher doses and longer term therapy.
Immunosuppressants: Drugs that suppress the immune system may be helpful in serious cases. Examples include azathioprine (Imuran, Azasan), mycophenolate (CellCept), leflunomide (Arava) and methotrexate (Trexall). Potential side effects may include an increased risk of infection, liver damage, decreased fertility and an increased risk of cancer. A newer medication, belimumab (Benlysta), also reduces lupus symptoms in some people. Side effects include nausea, diarrhea and fever.
Prevention of Lupus
There is no known way to prevent it, since there is no known cause as yet. You can help manage flare-ups though:
- Avoid known triggers such as sunlight, stress, and lack of sleep
- Manage your diet
- Get adequate exercise