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Lupus
Specialty	Immunology, rheumatology, dermatology

Systemic lupus erythematosus (SLE or lupus) is a chronic type III hypersensitivity autoimmune disease with potential type II involvement. It is potentially debilitating and sometimes fatal as the immune system attacks the body’s cells and tissue, resulting in inflammation and tissue damage. SLE can affect any part of the body, but often harms the heart, joints, skin, lungs, blood vessels and nervous system. Lupus is treatable, mainly with corticosteroids and immunesupressants, though there is currently no cure for it. The name lupus (Latin for "wolf"), is thought to derive from the crude similarity between the facial rash that some lupus patients develop and a wolf's face, though other explanations have been proposed.

History

The source of the name "lupus" is unclear. All explanations originate with the characteristic butterfly-shaped malar rash that the disease classically exhibits across the nose and cheeks. In various accounts, some doctors thought the rash resembled a wolf pattern. In other accounts doctors thought that the rash, which was often more severe in earlier centuries, created lesions that resembled wolf bites or scratches. Stranger still is the account that the term "Lupus" didn't come from Latin at all, but from the term for a French style of mask which women reportedly wore to conceal the rash on their faces.

The history of lupus erythematosus can be divided into three periods: the classical, neoclassical, and modern. The classical period began when the disease was first recognised in the Middle Ages and saw the description of the dermatological manifestation of the disorder. The term lupus is attributed to the twelfth century physician Rogerius, who used it to describe the classic malar rash. The neoclassical period was heralded by Moritz Kaposi's recognition in 1872 of the systemic manifestations of the disease. The modern period began in 1948 with the discovery of the LE cell and is characterised by advances in our knowledge of the pathophysiology and clinical-laboratory features of the disease, as well as advances in treatment. The LE cells are only found in 50-75% of SLE patients, and are also found in some patients with rheumatoid arthritis, scleroderma, and drug sensitivities. Because of this, the LE cell test is now performed only rarely and is mostly of historical significance.

Useful medication for the disease was first found in 1894, when quinine was first reported as an effective therapy. Four years later, the use of salicylates in conjunction with quinine was noted to be of still greater benefit. This was the best available treatment to patients until the middle of the twentieth century, when Hench discovered the efficacy of corticosteroids in the treatment of SLE.

Signs and symptoms

Common initial and chronic complaints are fever, malaise, joint pains, myalgias and fatigue. Because they are so often seen with other diseases, these signs and symptoms are not part of the diagnostic criteria for SLE. When occurring in conjunction with other signs and symptoms (below), however, they are considered suggestive.

Dermatological manifestations

As many as 30% of patients present with some dermatological symptoms (and 65% suffer such symptoms at some point), with 30% to 50% suffering from the classic malar rash (or butterfly rash) associated with the disease. Patients may present with discoid lupus (thick, red scaly patches on the skin). Alopecia, mouth, nasal, and vaginal ulcers, and lesions on the skin are also possible manifestations.

Musculoskeletal manifestations

Patients most often seek medical attention for joint pain, with small joints of the hand and wrist usually affected, although any joint is at risk. Unlike rheumatoid arthritis, SLE arthropathy is not usually destructive of bone, however, deformities caused by the disease may become irreversible in as many as 20% of patients.

Hematological manifestations

Anemia and iron deficiency may develop in as many as half of patients. Low platelet and white blood cell counts may be due to the disease or a side-effect of pharmacological treatment. Patients may have an association with antiphospholipid antibody syndrome (a thrombotic disorder) where autoantibodies to phospholipids are present in the patient's serum. Abnormalities associated with antiphospholipid antibody syndrome include a paradoxical prolonged PTT (which usually occurs in hemorrhagic disorders) and a positive test for antiphospholipid antibodies, the combination of such findings have earned the term "lupus anticoagulant positive". Another autoantibody finding in lupus is the anticardiolipin antibody which can cause a false positive test for syphillis.

Cardiac manifestations

Patients may present with inflammation of various parts of the heart, such as pericarditis, myocarditis and endocarditis. The endocarditis of SLE is characteristically non-infective (Libman-Sacks endocarditis), and involves either the mitral valve or the tricuspid valve. Atherosclerosis also tends to occur more often and advance more rapidly in SLE patients than in the general population.

Pulmonary manifestations

Lung and plura inflammation can cause pleuritis, pleural effusion, lupus pneumonitis, chronic diffuse interstitial lung disease, pulmonary hypertension, pulmonary emboli, pulmonary hemorrhage.

Renal involvement

Painless hematuria or proteinuria may often be the only presenting renal symptom. Acute or chronic renal impairment may develop with lupus nephritis, leading to acute or end stage renal failure. Because of early recognition and management of SLE, end stage renal failure occurs in less than 5% of patients.

Histologically, a hallmark of SLE is membranous glomerulonephritis with "wire loop" abnormalities. This finding is due to immune complex deposition along the glomerular basement membrane leading to a typical granular appearance in immunofluorescence testing.

Neurological manifestations

About 10% of patients may present with seizures or psychosis. A third may test positive for abnormalities in the cerebrospinal fluid.

Other rarer manifestations

Lupus gastroenteritis, lupus pancreatitis, lupus cystitis, autoimmune inner ear disease, parasympathetic dysfunction, retinal vasculitis, and systemic vasculitis.

T-cell abnormalities

Abnormalities in T cell signaling are associated with SLE, including deficiency in CD45 {phosphatase, increased expression of CD40 ligand.

Other abnormalities include:

• Increased expression of FcεRIγ, which replaces the sometimes deficient TCR ζ chain
• Increased and sustained calcium levels in T cells
• Moderate increase of inositol triphosphate
• Reduction in PKC phosphorylation
• Reduction in Ras-MAP kinase signaling
• Deficiencies in protein kinase A I activity

Diagnosis

Some physicians make a diagnosis on the basis of the ACR classification criteria (see below). The criteria, however, were established mainly for use in scientific research (i.e. inclusion in randomised controlled trials), and patients may have lupus despite never meeting the criteria.

Antinuclear antibody testing and anti-extractable nuclear antigen (anti-ENA) form the mainstay of serologic testing for lupus. Antiphospholipid antibodies occur more often in SLE, and can predispose for thrombosis. More specific are the anti-smith and anti-dsDNA antibodies. Other tests routinely performed in suspected SLE are complement system levels (low levels suggest consumption by the immune system), electrolytes and renal function (disturbed if the kidney is involved), liver enzymes and a full blood count.

Diagnostic criteria

The American College of Rheumatology (ACR) has established eleven criteria in 1982, which were revised in 1997, as a classificatory instrument to operationalise the definition of SLE in clinical trials. They were not intended to be used to diagnose individual patients and do not do well in that capacity. A patient must present with four of the eleven criteria, either simultaneously or serially, during a given period of observation, to be classified as having SLE — for the purposes of inclusion in clinical trials.

1. Malar rash (rash on cheeks)
2. Discoid lupus (red, scaly patches on skin which cause scarring)
3. Photosensitivity (adverse reaction to sunlight)
4. Mouth or nose ulcers
5. Arthritis
6. More than 0.5g per day protein in urine, or cellular casts seen in urine under a microscope.
7. Seizures or psychosis
8. Pleuritis (inflammation of the membrane around the lungs) or pericarditis (inflammation of the membrane around the heart)
9. Hemolytic anemia (low red blood cell count), leukopenia (low white blood cell count), lymphopenia (low lymphocyte count) or thrombocytopenia (low platelet count)
10. antinuclear antibody test (positive ANA), very sensitive (98%) but non specific.
11. Anti-Sm antibody or false positive serological test for syphilis or antiphospholipid antibody positivity, presence of Anti-ss DNA in 70% of patients.

A useful mnemonic for these 11 criteria is SOAP BRAIN MD: Serositis (8), Oral ulcers (4), Arthritis (5), Photosensitivity (3), Blood Changes (9), Renal involvement (proteinuria or casts) (6), ANA (11), Immunological changes (10), Neurological signs (seizures, frank psychosis) (7), Malar Rash (1), Discoid Rash (2).

Some patients may have SLE without four criteria and SLE is associated with manifestations other than those listed in the criteria. Dr Graham R.V. Hughes, an authority on lupus in the UK, has published alternative criteria to diagnose SLE in 1982.

Etiology

SLE is known as "the great imitator" because its symptoms vary so widely it often mimics or is mistaken for other illnesses, and because the symptoms come and go unpredictably. Diagnosis can be elusive, with patients sometimes suffering unexplained symptoms and untreated SLE for years. Previously believed to be a rare disease, Lupus has seen an increase in awareness and education since the 1960s. This has helped many more patients get an accurate diagnosis making it possible to estimate the number of people with lupus. In the United States alone, an estimated 270,000 to 1.5 million people have lupus, making it more common than cystic fibrosis or cerebral palsy. The disease affects both females and males, thoug young women are diagnosed nine times more often than men. SLE appears to occur with much greater severity among African-American women who suffer more severe symptoms, as well as a higher mortality rate. Worldwide, a conservative estimate states that over 5 million people have lupus.

The exact cause of the disease is unknown and there is no consensus on whether it is a single condition or a group of related diseases. SLE is a chronic inflammatory disease believed to be a type III hypersensitivity response, which is characterised by the body's production of antibodies against the nuclear components of its own cells. There are three mechanisms by which lupus is thought to develop: genetic predisposition, environmental triggers and drug reaction (drug-induced lupus).

Genetics

The first mechanism may arise genetically. Research indicates that SLE may have a genetic link. Several genes need to be affected for lupus to occur, and the most important genes are located on chromosome 6. These mutations may occur randomly (de novo) or be inherited. Additionally, people with SLE have an altered RUNX-1 binding site, which may be either cause or contributor (or both) to the condition. Altered binding sites for RUNX-1 have also been found in people with psoriasis and rheumatoid arthritis.

Environmental triggers

The second mechanism may be due to environmental factors. These factors can not only exacerbate existing lupus conditions, but can trigger the initial onset. They include certain medications (such as some antidepressants and antibiotics), extreme stress, exposure to sunlight, hormones, and infections. Some researchers have sought to find a connection between certain infectious agents (viruses and bacteria), but no pathogen can be consistently linked to the disease. UV radiation has been shown to trigger the photosensitive lupus rash, but some evidence also suggests that UV light is capable of altering the structure of the DNA, leading to the creation of autoantibodies. Some researchers have found that women with silicone gel-filled breast implants can produced antibodies to their own collagen, but it is not known how often these antibodies occur in the general population and there are no data that show these antibodies cause connective tissue diseases such as lupus.

Non-SLE forms of lupus

There are two other forms of lupus: discoid (cutaneous) lupus and drug-induced lupus erythematosus. Discoid lupus is limited to skin symptoms and is diagnosed via biopsy of skin rash on the face, neck or scalp. Often an Anti-nuclear antibody (ANA) test for discoid patients is negative or a low-titre positive. About 10% of discoid lupus patients eventually develop SLE. Drug-induced lupus erythematosus is a reversible condition that usually occurs in patients being treated for a long-term illness. Drug-induced lupus mimics systemic lupus. However, symptoms of drug-induced lupus generally disappear once a patient is taken off of the medication which triggered the episode. There are about 400 medications currently in use that can cause this condition, though the most common drugs are procainamide, hydralazine and quinidine.

The five major forms of dominantly inherited porphyrias (acute intermittent porphyria, porphyria cutanea tarda, hereditary coproporphyria, variegate porphyria and erythropoietic protoporphyria) have been detected in systemic lupus erythematosus and discoid lupus patients over the past 50 years.

Porphyrias are complex genetic disorders that impact the enzymes responsible for building heme, a component needed in heme proteins. Porphyrias are ecogenic disorders requiring both environmental and genetic backgrounds to manifest with a variety of symptoms and medical complications. They are noted for photosensitivity and have been associated with transient and permanent production of autoantibodies.

Medical historians have theorized people with porphyrias generated folklore stories of vampires and werewolves due to the photosensitivity, scarring, hair growth and porphyrin brownish-red stained teeth in severe recessive forms of porphyria or combinations of the disorders known as dual, homozygous or compound heterozygous porphyrias.

Patients with acute hepatic porphyrias (acute intermittent porphyria, hereditary coproporphyria, variegate porphyria) have been detected in lupus patients with severe life-threatening "lupus" complications known as neurolupus. Symptoms are identical to acute hepatic porphyria attacks and include seizures, psychosis, peripheral neuropathy and syndrome of inappropriate antidiuretic hormone (SIADH) associated with dangerously low sodium levels (hyponatremia).

Porphyria attacks require intervention with intravenous glucose, heme preparations and the discontinuation of dangerous porphyrinogenic drugs including antiseizure drugs.

Several other lupus complications have been associated with porphyrias including pancreatitis and pericarditis.

Physicians should have a high degree of suspicion of porphyrias in all lupus cases and act accordingly when patients are in a medical crisis that may be due to an underlying acute hepatic porphyria. Drug-induced lupus and photosensitivity warrant an investigation for an underlying porphyria since multiple drug reactions are a hallmark complication of porphyrias. Patients with both lupus and porphyrias should avoid porphyrinogenic drugs and hormone preparations. Cyclical attacks of porphyria can occur with natural hormonal cycles and pregnancy.

Porphyrin testing should be performed on urine, stool/bile and blood to detect all types of porphyrias. Repeat testing should be performed in suspicious cases. Appropriate enzyme tests or DNA testing should also be pursued to obtain a complete diagnosis which could include a dual porphyria.

Pathophysiology

Abnormalities in apoptosis

• Apoptosis is increased in monocytes and keratinocytes
• Expression of Fas by B cells and T cells is increased
• There are correlations between the apoptotic rates of lymphocytes and disease activity

Tingible body macrophages (TBMs) are large phagocytic cells in the germinal centers of secondary lymph nodes. They express CD68 protein. These cells normally engulf B cells which have undergone apoptosis after somatic hypermutation. In some patients with SLE, significantly fewer TBMs can be found, and these cells rarely contain material from apoptotic B cells. Also, uningested apoptotic nuclei can be found outside of TBMs. This material may present a threat to the tolerization of B cells and T cells,

Dendritic cells in the germinal center may endocytose such antigenic material and present it to T cells, activating them. Also, apoptotic chromatin and nuclei may attach to the surfaces of follicular dendritic cells and make this material available for activating other B cells which may have randomly acquired self-specificity through somatic hypermutation.

Treatment

SLE is a chronic disease with no cure, so medications that modulate the immune system (primarily corticosteroids and immunosuppressants) are used to control the disease and prevent flares. Disease-modifying antirheumatic drugs (DMARDs) are used preventively to suppress flares, the process of the disease, and reduce steroid use, while corticosteroids are used to treat flares. DMARDs commonly in use are the antimalarials (e.g. hydroxychloroquine, methotrexate and azathioprine). Hydroxychloroquine (trade name Plaquenil) is an FDA approved anti-malarial used for constitutional, cutaneous, and articular manifestations, while Cyclophosphamide is used for severe glomerulonephritis or other organ-damaging complications.

Patients who require steroids frequently may develop obesity, diabetes and osteoporosis. Due to these side effecs, steroids are avoided if possible. Other measures such as avoiding sunlight or covering up with sun protective clothing can also be effective in preventing problems due to photosensitivity.

In 2005, CellCept became accepted for treatment of lupus kidney disease. However, corticosteroids, depending on the dosage, can bring unwanted side effects such as a puffy face, an unusually large appetite and difficulty sleeping. Those side effects can subside if and when the large initial dosage is reduced, but long term use of even low doses can cause elevated blood pressure and cataracts.

Treatment Research

Other immunosuppressants and autologous stem cell transplants are under investigation. Recently, treatment that is more specific in modifying a particular subset of the immune cells (e.g. B- or T- cells) or certain protein they secrete (cytokines) has been gaining attention. Research into new treatments has recently been accelerated by genetic discoveries, especially mapping of the human genome. According to a June 2006 market analysis report by Datamonitor, treatment for SLE could be on the verge of a breakthrough as there are numerous late-Phase trials currently being carried out.

Alternative medicine

Traditional Chinese Medicine may be useful in the treatment of lupus. A 1985 study on lupus and acupuncture reported improvement of lupus sufferers over matched controls, though there was no placebo group for comparison. It is possible that acupuncture may be useful for the treatment some of the symptoms of lupus, but there needs to be more research done before a definitive statement can be made regarding alternative medicine.

Epidemiology

Although SLE can occur in anyone at any age, it is most common in women of childbearing age. It affects 1 in 4000 people in the United States, with women suffering five to fifteen times more often than men. The disease appears to be more prevalent in women of African, Asian, Hispanic and Native American origin but this may be due to socioeconomic factors. People with relatives who suffer from SLE, rheumatoid arthritis or thrombotic thrombocytopenic purpura are at a slightly higher risk than the general population.

Prognosis

In the 1950s, most patients diagnosed with SLE lived fewer than five years. Advances in diagnosis and treatment have improved survival to the point where over 90% of patients now survive for more than ten years and many can live relatively asymptomatically. The most common cause of death is infection due to immunosuppression as a result of medications used to manage the disease, though renal disease also causes significant morbidity. Prognosis is normally worse for men and children than for women and if symptoms are present after age 60, the disease tends to run a more benign course.

The Anti-dsDNA antibody test is the only marker of prognosis in lupus, while Anti-Sm (Anti Smith) is the most sensitive.

Research

Lupus research has dramatically increased in recent years. The largest research funding organization in the United States, as of 2006, is the Alliance for Lupus Research. New York University is a main center for research into neonatal lupus - a form of lupus transfered from mother to fetus. Neonatal lupus often manifests as heart conduction defects and a skin rash. The conduction defects can be minor, but can also be serious, requiring the placement of a pacemaker to regulate heart rhythm.

Famous patients

• Ferdinand Marcos, former Philippine dictator.
• Flannery O'Connor, American fiction writer.
• Hugh Gaitskell, British politician.
• Elaine Paige, British actress and singer.
• Michael Jackson, famous singer/songwriter, was supposedly diagnosed with discoid lupus and vitiligo in the early 1980s.

• Seal, a British musician, had non-SLE lupus in his childhood.
• Millie, the pet dog of former President George H. W. Bush & Barbara Bush, was diagnosed with discoid lupus erythematosus.
• Charles Kuralt, former anchor of CBS Sunday Morning
• J Dilla, a hip-hop producer and beatmaker.
• Inday Ba (also known as N'Deaye Ba), a Swedish-born actress. She died from complications of lupus, aged 32.
• Caroline Dorough-Cochran, sister of Howie D. of the Backstreet Boys, who founded the Dorough Lupus Foundation in her memory.
• Mercedes Yvette, runner up of season two of America's Next Top Model

See also

• abzyme
• antinuclear antibody
• discoid lupus erythematosus in dogs
• Drug-Induced Lupus Erythematosus

Footnotes

1. University of South Carolina lecture on immunology
2. NIM encyclopedic article on the LE cell test
3. Yu Asanuma, M.D., Ph.D., Annette Oeser, B.S., Ayumi K. Shintani, Ph.D., M.P.H., Elizabeth Turner, M.D., Nancy Olsen, M.D., Sergio Fazio, M.D., Ph.D., MacRae F. Linton, M.D., Paolo Raggi, M.D., and C. Michael Stein, M.D. (2003). "Premature coronary-artery atherosclerosis in systemic lupus erythematosus". New England Journal of Medicine. 349 (Dec. 18): 2407–2414. PMID 14681506 Abstract (full text requires registration).{{cite journal}}: CS1 maint: multiple names: authors list (link)
4. Bevra Hannahs Hahn, M.D. (2003). "Systemic lupus erythematosus and accelerated atherosclerosis". New England Journal of Medicine. 349 (Dec. 18): 2379–2380. PMID 14681501 Extract (full text requires registration).
5. Mary J. Roman, M.D., Beth-Ann Shanker, A.B., Adrienne Davis, A.B., Michael D. Lockshin, M.D., Lisa Sammaritano, M.D., Ronit Simantov, M.D., Mary K. Crow, M.D., Joseph E. Schwartz, Ph.D., Stephen A. Paget, M.D., Richard B. Devereux, M.D., and Jane E. Salmon, M.D. (2003). "Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus". New England Journal of Medicine. 349 (Dec. 18): 2399–2406. PMID 14681505 Abstract (full text requires registration).{{cite journal}}: CS1 maint: multiple names: authors list (link)
6. Rheumatology.org article on the classification of rheumatic diseases
7. Revision of Rheumatology.org's diagnostic criteria
8. Alternative criteria for diagnosis of Lupus in the United Kingdom
9. Lupus: The Great Imitator
10. Excerpt from NINDS Neurological Sequelae Of Lupus Information Page
11. Lupus and African-American women
12. FDA aticle on breast implatns
13. Lead Discovery article on treatment of Lupus
14. Review of different alternative treatments for lupus
15. Hospital for Special Surgery article on acupuncture and lupus

References

• Yu Asanuma, M.D., Ph.D., Annette Oeser, B.S., Ayumi K. Shintani, Ph.D., M.P.H., Elizabeth Turner, M.D., Nancy Olsen, M.D., Sergio Fazio, M.D., Ph.D., MacRae F. Linton, M.D., Paolo Raggi, M.D., and C. Michael Stein, M.D. (2003). "Premature coronary-artery atherosclerosis in systemic lupus erythematosus". New England Journal of Medicine. 349 (Dec. 18): 2407–2414. PMID 14681506 Abstract (full text requires registration).{{cite journal}}: CS1 maint: multiple names: authors list (link)
• Bevra Hannahs Hahn, M.D. (2003). "Systemic lupus erythematosus and accelerated atherosclerosis". New England Journal of Medicine. 349 (Dec. 18): 2379–2380. PMID 14681501 Extract (full text requires registration).
• Mary J. Roman, M.D., Beth-Ann Shanker, A.B., Adrienne Davis, A.B., Michael D. Lockshin, M.D., Lisa Sammaritano, M.D., Ronit Simantov, M.D., Mary K. Crow, M.D., Joseph E. Schwartz, Ph.D., Stephen A. Paget, M.D., Richard B. Devereux, M.D., and Jane E. Salmon, M.D. (2003). "Prevalence and correlates of accelerated atherosclerosis in systemic lupus erythematosus". New England Journal of Medicine. 349 (Dec. 18): 2399–2406. PMID 14681505 Abstract (full text requires registration).{{cite journal}}: CS1 maint: multiple names: authors list (link)

External links

• S.L.E. Lupus Foundation
• Lupus Foundation of America
• Lupus Research Institute
• London Lupus Centre - Treatment, Diagnosis, Research
• Alliance for Lupus Research
• Lupus Erythematosus of the skin, New Zealand Dermatological Society Incorporated
• Lupus Clinical Overview
• Lupus UK
• Lupus Patiënten Groep NL
• History of Lupus (NZ Lupus Trust)
• Lupus Patients Understanding & Support (LUPUS)
• The LuPUS Message Board
• Lupus International
• BLIPS Clinical Software for assessing and monitoring lupus patients
• Handout on Health: Systemic Lupus Erythematosus

Also see

• Arthritis
• Rheumatology
• Nephrology
• Autoimmune diseases