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Lupus
SpecialtyImmunology, rheumatology, dermatology Edit this on Wikidata

Systemic lupus erythematosus (SLE or lupus) is a chronic, potentially debilitating or fatal autoimmune disease in which 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 (rheumatological), skin, lungs, blood vessels and brain/nervous system. Lupus is treatable, mainly with immunosuppression, though there is currently no cure for it.

The standard treatment has been a limited group of drugs (primarily corticosteroids, anti-malarials, and chemotherapy drugs). Plaquenil (hydroxychloroquine sulfate) is currently the only FDA approved anti-malarial for treating SLE. In 2005, CellCept became accepted for treatment of lupus kidney disease.

Research into more modern treatments has recently begun and is accelerated by genetic discoveries, especially mapping of the human genome. SLE is known as "the great imitator", as it often mimics other illnesses because the symptoms come and go unpredictably. Diagnosis can be elusive, with patients sometimes suffering unexplained symptoms and untreated SLE for years. Increased awareness and education about lupus since the 1960s has helped many more patients get an accurate diagnosis and made it possible to estimate the number of people with lupus. Lupus was previously believed to be a rare disease. 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 primarily affects young women, although men can be diagnosed with lupus. World-wide, a conservative estimate states that over 5 million people have lupus.

SLE was called lupus (Latin for "wolf"), perhaps due to a crude similarity between the facial rash that some lupus patients develop, and a wolf's face, although various explanations have been proposed.

Etiology

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 (serum sickness) 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 causes 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 causes
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. Similarly, some researchers have found that some women with silicone gel-filled breast implants produced antibodies to their own collagen (a connective tissue protein), but we do not know how often these antibodies occur in the general population, and there are no data that show these antibodies cause CTDs (Connective Tissue Diseases) such as lupus.
Non-SLE forms of lupus
There are two other forms of lupus: discoid lupus and drug-induced lupus. 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 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

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.

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, 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: 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. (Asanuma et al 2003, Bevra 2003, Roman et al 2003).
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.
Also associated with SLE is increased expression of FcεRIγ, which replaces the TCR ζ chain, which is deficient in some SLE patients.
Other abnormalities include:

And deficiencies in:

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 is the anti-smith antibody. 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. Anti-DNA antibody sensitive but not specific; almost all patients with SLE have elevated serum ANA levels.
  11. Anti-Sm antibody or false positive serological test for syphilis or antiphospholipid antibody positivity
  12. Anti-ss DNA (in 70%)
  13. Antihistone Abs (in 70%) are present in 100% of drug-induced lupus. If negative drug induced lupus can be exluded.
  14. Positive fluorescence antinuclear antibody test (positive ANA)
  15. Prolonged PTT
  16. Anticardiolipin and lupus anticoagulant
  17. Complement levels are usually decreased

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.

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).

Treatment

SLE is a chronic disease with no cure. There are, however, some medications, such as corticosteroids and immunosuppressants which can control the disease and prevent flares. Flares are typically treated with steroids, with DMARDs (disease-modifying antirheumatic drugs) to suppress the disease process, reduce steroid needs and prevent flares. DMARDs commonly in use are the antimalarials (e.g. hydroxychloroquine or methotrexate) and azathioprine. Hydroxychloroquine is used for constitutional, cutaneous, and articular manifestations. Cyclophosphamide is used for severe glomerulonephritis or other organ-damaging complications. Renal disease produces the most significant morbidity.

Patients who require steroids frequently may develop obesity, diabetes and osteoporosis. Hence, steroids are avoided where possible.

Measures such as avoiding sunlight (to prevent problems due to photosensitivity) may also have some effect.

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.

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. A person with a parent or sibling with the condition has a 10% chance of developing the condition. Only 5% of children born to a parent with lupus will develop the condition.

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. 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.


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 (although use of these cells as diagnostic indicators has now been largely abandoned) and is characterised by advances in our knowledge of the pathophysiology and clinical-laboratory features of the disease, as well as advances in treatment.

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.

Famous patients

File:Michael Jackson and DrMetzgen'03.jpeg
Michael Jackson presents award to Dr. Allan Metzgen, who treats the artist over vitiligo and discoid lupus, at The 5th Annual Lupus LA Gala, sponsored by Lupus Research Institute.

See also

References

External links

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