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 most often harms the kidneys (lupus
nephritis), heart, joints (rheumatological), skin, lungs,
blood vessels and brain/nervous system. Lupus is
treatable, though there is currently (2006) no cure for
it.
The standard treatment, for decades, has been a limited
group of drugs (primarily corticosteroids and chemotherapy
drugs). 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." Symptoms often mimic other
illnesses. And because they 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. 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 genes may occur randomly or be a
result of heredity. 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 owing 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.
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 40 medications currently in use that can cause this
condition, though the most common drugs are procainamide,
hydralazine and quinidine.
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.
Complement pathway
SLE is associated with
defects in
lectins and the
classical complement pathway.
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 (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.
Cardiac 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.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.
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 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.
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
in 1982.
Current 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) and azathioprine. Cyclophosphamide is
used for severe nephritis or other organ-damaging
complications.
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.
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.
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