Lupus erythematosus

Information and facts about Autoimmune diseases.

Lupus erythematosus (also known as systemic lupus erythematosus - SLE) is an autoimmune disorder in which antibodies are created against the patient's own DNA. It classically presents with a butterfly-shaped malar rash, causing a wolf-like appearance (Lupus is Latin for wolf).

Signs and symptoms

Common initial and chronic complaints are fever, malaise, myalgias, fatigue and weight loss. Because they are so often seen with other diseases, these signs and symptoms are not part of the diagnostic criteria for SLE, but when occurring in conjunction with other signs and symptoms, 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), but only 30% to 50% suffer the classic malar (or ?butterfly?) rash associated with the disease. Patients may present with discoid lupus, thick red scaly patches on the skin. Alopecia, mouth 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.

Cardiac manifestations

Patients may present with inflammation of various parts of the heart: pericarditis, myocarditis and endocarditis. There may be immune complexes on the mitral valve of the heart, where bacteria can accumulate. Atherosclerosis also tends to occur more often and advance more rapidly in SLE patients than in the general population.

Renal involvement

Painless hematuria or proteinuria may often be the only presenting renal symptom. Because of early recognition and management of SLE, end stage renal failure occurs in less than 5% of patients.

Neurological manifestations

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

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:

increased and sustained calcium levels in T cells
moderate increase of inositol triphosphate
reduction in PKC phosphorylation
reduction in Ras-MAP kinase signalling
And deficiencies in:

protein kinase A I activity

Diagnosis

Some physicians make a diagnosis on the basis of the ARC 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.

Classification

The American College of Rheumatology has established eleven criteria in 1982[1] (http://www.rheumatology.org/publications/classification/index.asp?aud=mem), which were revised in 1997[2] (http://www.rheumatology.org/publications/classification/SLE/1982SLEupdate.asp?aud=mem), 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.

Malar rash (rash on cheeks)
Discoid lupus (red, scaly patches on skin which cause scarring)
Photosensitivity (adverse reaction to sunlight)
Mouth ulcers
Arthritis
More than 0.5g per day protein in urine, or cellular casts seen in urine under a microscope.
Seizures or psychosis
Pleuritis (inflammation of the membrane around the lungs) or pericarditis (inflammation of the membrane around the heart)
Hemolytic anemia (low red blood cell count), leukopenia (low white blood cell count), lymphopenia (low lymphocyte count) or thrombocytopenia (low platelet count)
Anti-DNA antibody, anti-Sm antibody or false positive serological test for syphilis or antiphospholipid antibody positivity
Positive fluorescence antinuclear antibody test (positive ANA)
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[3] (http://www.lupus-support.org.uk) in 1982.

Pathophysiology

Causes

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. 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. Certain medications (such as some antidepressants) and environmental factors (such as exposure to sunlight) have been found to exacerbate symptoms.

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.

Complement pathway

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

Epidemiology

Although SLE can occur in anyone at any age, it is most common in women of childbearing age. It affects one in 3000 people in the United States, with women suffering five to nine times more often than men. The disease appears to be more prevalent in women of African and Hispanic origin but this may be due to socioeconomic factors. People with relatives who suffer from SLE, rheumatoid arthritis or thrombotic thrombocytopenic purpura are at higher risk than the general population.

Prognosis

In the 1950s, most patients diagnosed with SLE lived less 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 present after age 60, the disease tends to run a more benign course.

History

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 thirteenth century physician Rogerius, who used it to describe the classic malar rash. The neoclassical period was heralded by Moritz Kohn 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 pathopysiology 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 conjuction with quinine was noted to be of still greater benefit. This was the best available to patients until the middle of the twentieth century when Hench discovered the efficacy of corticosteroids in the treatment of SLE.

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