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LUPUS
What is lupus?
Lupus is an autoimmune disease caused by anti-DNA antibodies that
attack the body's own healthy cells. The disease is characterized
by constant IgG production directed at self antigens in all
nucleated cells (Janeway, 1999). This leads to inflammation and
damage of body tissues and the common symptoms of fatigue,
painful or swollen joints, unexplained fever, skin rashes, and
kidney problems. In accordance with the pain in the joints and
muscles that results from lupus, the disease has been classified
as a rheumatic disease. Lupus is used as a broad term to describe
several forms of the disease, but is most often used to refer to
systemic lupus erythematosus (SLE), which can effect various
parts of the body and cause an array of symptoms. Lupus affects
over one million individuals and 90% of those affected are women.
People of all races may get lupus; however, lupus is three times
more common in black women than in white women. As many as 1 in
250 young black women will get the disease (NIAMS, 1999).The
disease received its name in 1851 based on the definitions of
lupus ("wolf") and erythematosus ("redness")
and the appearance of facial rashes that looked like the bite of
a wolf on individuals that had this disease (NIAMS, 1999).
Figure 1: This is a picture of a typical malar rash, also called
a "butterfly" rash, that appears on patients with lupus.
Permission to use this figure is pending from the author of the
website and will be removed if permission is not granted. Click here to
go to the website that contains this picture.
What are the types of infection in SLE?
There are two major categories of lupus. The first category
includes infections caused by organisms, which can induce
infection in those infected with lupus as well as within the
general population. These organisms include streptococcus and
staphylococcus.
The second category consists of infections are caused by
organisms that have the potential for inducing disease only when
ones immune system is weakened. Most opportunistic
infections are fungal, parasitic or protozoan. The most common
infections that lupus patients contract involve the respiratory
tract, skin and urinary tract. These infections usually do not
require hospitalization. Actually, only a few lupus patients need
to be hospitalized for their infections (Mills, 1994).
What are the different subsets of SLE?
Discoid lupus is an illness characterized by a non-photosensitive,
chronic and potentially scarring skin disease. This illness is
usually unaccompanied by antinuclear antibodies (ANA) or other
autoantibodies. Perhaps 10% of patients with discoid lupus will
develop the systemic illness (Mills, 1994).
Drug-induced lupus is usually characterized by fever,
hematological abnormalities such as an autoimmune hemolytic
anemia or autoimmune thrombocytopenia, or serositis. Skin, renal
and neurologic manifestations are uncommon.
Neonatal or congenital lupus occurs when the transplacental
acquisition of autoantibodies, specifically anti-Ro (SS-A), a 60-kD
ribonucleoprotein, produces in the neonate a transient
photosensitive rash, confential complete heart block,
thrombocytopenia or hepatobiliary dysfunction (Mills, 1994).
ANA negative or Ro lupus is defined by the absence of an ANA and
the present of a lupus-like illness. This disorder is often
induced by a partially photosensitive skin rash referred to as
subacute cutaneous lupus erythematosus. These patients often
demonstrate anti-Ro antibodies, and these patients may be ANA
negative (Hahn, 1987).
Figure 2: This is an example of a rash on the back of an
individual with subacute cutaneous lupus erythematosus.
Permission is pending from the author and will be removed from
the site if permission is not granted. Click here
to go to the website that contains this picture.
What's Involved?
SLE is an autoimmune disease
characterized by an elevated serum concentration of
immunoglobulin G (IgG) antibodies directed towards self cellular
nuclear elements. Small immune complexes that are not cleared by
splenic and hepatic complement and Fc receptors tend to become
trapped in blood vesels of the kidney and joints, leading to the
inflammation that results from the disease. These immune
complexes can also lead to the production of proinflammatory
cytokines that elicit a variety of physiological responses (Kelley,
1997).
For example, when mice are treated with a human anti-DNA
monoclonal antibody, the result is an elevation in both
interleukin-1 and TNF-a. These findings, in addition to the fact
that high doses of glucocorticoids suppress the synthesis of IL-1
and often pacify many of the symptoms of SLE, is consistent with
the hypothesis of a prominent role for inflammatory cytokines in
the pathogenenesis of this desease (Segal, 1995). These cytokines
synergize in many ways, including their ability to cause symptoms
associated with lupus. For example, pain may be caused in joints
due to the destructive effects of IL-1 and TNF-a (Kelley, 1997).
What are the effects of
lupus?
General Symptoms
Ninety percent of patients with SLE experience fatigue. A less
common, but more serious, constitutional feature of SLE is
persistent fever and weight loss (Mills, 1994). Eighty percent of
patients with SLE will present with involvement of the skin or
joints. Common symptoms include a photosensitive rash and
arthritis. Patients may also experience a fever accompanied by a
single organ involvement, such as inflammatory serositis,
glomerulonephritis, neuropsychiatric disturbance or hematological
disorder (autoimmune hemolytic anemia or thrombocytopenia).
Severe, generalized lupus involving multi-organ involvement
rarely occurs (Hahn, 1987).
Musculoskeletal Effects
Ninety percent of patients with SLE have musculoskeletal symptoms.
Arthralgia is a typical clinical manifestation in SLE patients.The
joints most commonly involved are the proximal interphalangeal,
metacarpophalangeal, wrist, and knees (Hahn, 1987).
When arthritis occurs in SLE, it is usually the consequence of
periarticular inflammation, involving the tendons, which can lead
to Jaccouds arthropathy. This is different than rheumatoid
arthritis, where lupus is rarely accompanied by frank articular
erosions. With inflammatory muscle disease, there is usually an
elevation of the muscle enzymes, such as creatine phosphokinase,
lactate dehydrogenase or aldolase (Hahn, 1987).
Mucosal/Epidermal Effects
Mucosal ulcers occurs in 30% of patients with SLE. They most
often occur on the hard or soft palate or on the nasal septum.
The ulcers are usually painless unless there is a secondary
infection, such as oral candidiasis. It is controversial whether
the ulcers represent a simple inflammatory mucositis or a frank
vasculitis of the mucous membranes (McKhann, 1994).
Dermatologic Effects
SLE must be distinguished from discoid lupus erythematosus (DLE)
which affects the skin (but only in sun exposed regions) and is
unlikely to be associated with systemic illness, such as renal
disease. A biopsy of sun exposed skin that is not involved with a
rash will demonstrate immune complex deposition with SLE, but not
with DLE.
Eighty percent of patients with SLE have dermatological
manifestations during the course of their illness. The acute
cutaneous flare-up causes a photosensitive rash, which often has
a butterfly appearance, because the rash involves the bridge of
the nose and malar areas of the face. Photosensitivity is less
common in patients of color but occurs in 50% of all patients
with SLE. The rash of subacute cutaneous lupus is observed in
anti-Ro positive patients. This eruption is intermediately
photosensitive and can either have an annular, polycyclic
appearance (Kotzin, 1986).
Twenty-five percent of patients with SLE have discoid skin
lesions. These lesions are often on the face or the inner pinna
of the ear, but the lesions are not photosensitive. These lesions
are characterized clinically by follicular plugging, skin atrophy,
and scaling (Kotzin, 1986).
Alopecia occurs in 50% of patients. Typically this is manifest as
reversible hair thinning during periods of disease activity,demonstrated
by the ease with which hair can be plucked from the scalp.
Discoid lesions involving the scalp leads to scarring alopecia (Kotzin,
1986).
Figure 3: A severe inflammatory skin reaction in the upper
dermis of a patient with SLE in which the basal layer is
undergoing
vacuolization and dissolution, and there is purpura with RBC's in
the upper dermis (which are the reason for the rash). Click here
to go to the website that has this picture. Permission to use
this picture is pending from the author of the website and will
be removed if permission is not granted.
Hematological Effects
Anemia of chronic inflammation is a common feature of aggravated
SLE. Coombs positive hemolytic anemia with an acute declining
hematocrit and reticulocytosis is a characteristic of SLE, but
only appears in 10% of patients (Hahn, 1987).
Autoimmune thrombocytopenia purpura can be a presenting feature
of SLE or occur at any time in the course of the illness.
Thrombocytopenia as a consequence of the antiphopholipid antibody
syndrome has also been described in SLE. Leukopenia with
lymphopenia is also a characteristic feature of SLE (Hahn, 1987).
Renal Effects
Kidney disease occurs in about 50% of patients--the consequence
of the deposition of immune complexes containing anti-DNA in the
kidney. Serum antibodies to anti-DNA are a marker for the
development of renal disease (Mills, 1994).
Figure 4: This is a picture of the thickened capillary walls
in the patient with lupus nephritis. This is what leads to renal
failure in those individuals with the disease. Permission to use
this picture is pending and it will be removed if permission is
not granted. Click here
to go to the website that has this picture.
Effects on the Central Nervous System
Neuropsychiatric complications occur in 50% of SLE patients and
include acute and chronic, and localized and diffuse
manifestations. Twenty-five percent of patients with lupus
experience seizures. Diffuse cerebral dysfunction can result in
organic effective disorder, personality disorder, psychosis, or
coma. Vascular or migraine headaches occur in 10% of lupus
patients. Recurrent involvement of the central nervous system may
result in an organic brain syndrome and dementia (Bluestein, 1992).
Cardiac Effects
Active SLE can be accompanied by coronary artery vasculitis and,
on rare occasion, this has produced myocardial infarction. There
is an increased incidence of atherosclerotic heart disease in SLE,
including in premenopausal women. This may be related to coronary
artery pathology initiated by immune complex deposition. SLE
patients with the secondary antiphospholipid antibody syndrome
also develop myocardial infractions but on the basis of bland
coronary artery thrombosis (Briley et al., 1989).
Gastrointestinal Effects
Nonspecific inflammatory liver disease has been described in
lupus. Progression to cirrhosis as a consequence of inflammatory
liver disease in SLE is rare.
Secondary Antiphospholipid Antibody
Syndrome
What are antiphospholipid antibodies and what is their role in
patients with lupus?
The term antiphospholipid antibodies is used for antibodies
responsible for the lupus anticoagulant test, as well as those
detected in the anticardiolipin ELISA (Harris, 1985).
Antiphospholipid antibodies (aPL) are part of a group of
antibodies that are associated with problems relating to abnormal
blood clotting such as miscarriages, deep vein thromboses,
pulmonary emboli, and strokes. They may also be related to the
presence of migraine headaches and low platelet counts (thrombocytopenia).
They can be found in the blood of some people with lupus and
other autoimmune diseases and occasionally in people without any
other known disease. A variety of blood tests are used to detect
the presence of these antibodies.
Patients with SLE have an increased incidence of the
antiphospholipid antibody syndrome. This syndrome is defined by
the co-occurrence of thrombotic events and the presence of
autoantibodies against negatively charged phospholipid, such as a
lupus anticoagulant, or anti-cardiolipin antibody (Alarcón-Segovia
et al., 1989). This syndrome occurs most frequently in patients
with high titer IgG anti-cardiolipin antibodies or lupus
anticoagulant. Patients with this disorders are at risk for
recurrent arterial and venous thrombosis, thrombocytopenia, and
fetal wastage. The mechanisms of this prothrombotic diathesis are
uncertain, but these autoantibodies bind to target antigens on
endothelial cells, platelets or coagulation factors producing a
hypercoaguable state (Asherson et al., 1989).
Is Lupus Inherited?
A question frequently posed by expectant mothers out of concern
for themselves and their future newborns, the answer, however, is
not yet clear. It is true that the inheritance of genes from our
parents is important in the development of lupus, but the answer
is much more complicated than a simple yes. Research
related to lupus suggests that genetics does play an important
role in determining those individuals that will be affected by
the disease. It is estimated that four to six or more genes must
be combined for a person to inherit a susceptibility to acquire
lupus (Mills, 1994). Therefore, it is nearly impossible to
inherit all the genes necessary to develop lupus from a single
parent and this is one reason why it is unusual for lupus to
occur in multiple generations of a family. If only some of the
lupus genes are inherited, a person may test positive for some of
the immunological tests, such as the antinuclear antibody (ANA)
test, but may not actually have lupus. A positive ANA occurs in
up to one third of healthy family members of lupus patients (Mills,
1994).
Important genetic information in SLE is located on the short arm
of chromosome #6. The genes on chromosome #6 have many complex
functions. Some regulate complement components, which, when
missing, a milder form of lupus, which usually lacks kidney
involvement, may develop. Complement genes are important but they
are not the whole story in the development of this form of lupus.
For example, many susceptible individuals who lack these genes
for complement never develop lupus at all (Mills, 1994).
Another important area on the short arm of chromosome #6 is the
human leukocyte antigen (HLA) region. It is located next to the
area for complement genes. The HLA area has been very thoroughly
studied since it is used to match donors genetically to
recipients for organ transplants. it is further divided into
smaller regions called HLA-A, HLA-B, HLA-C, HLA-DR, HLA-DQ. In
lupus patients there is an increased frequency of the HLA genes
called Al, B8, Dr2, or Dr-3 and DQ1. Associations between genes
and diseases such as lupus are established by comparing lupus
patients to a normal or control population.
Particular HLA markers found in white lupus patients (on whom the
majority of studies have focused) have not been shown to be
present in black patients or Japanese patients with lupus. The
reasons for these differences are not clear. There may be other
as yet unknown genes or there may also be important genes on
other chromosomes, which play a part in making a person
susceptible to developing lupus (McKhann, 1994).
The newest research methods now being used to study genetics come
from the field of molecular biology. They are redefining the way
in which we look at the genetics of disease. When methods of
molecular biology are used to study the HLA system in various
diseases, we are finding that what looked like a specific HLA
type, by our current standard tests, in reality is slightly
different and Much more complex. This methodology should lead to
new important findings, both in genetics and in lupus. Another
way of studying the genetics of lupus is by looking at families
in which lupus occurs in more than one member. Familial cases are
reported in approximately 10% of the lupus population (McKhann,
1994). The most thoroughly studied family association is between
twins. If one of a pair of identical twins has lupus, the other
will develop it more than two thirds (69%) of the time. If a
fraternal or non-identical twin has lupus, the other twin has
only a 5% chance of developing it. It is obvious that genetics
are important, since the frequency of developing lupus is so much
higher in identical twins than in fraternal twins when one of the
twins already has lupus. Genetic factors cannot be the only
answers, however, or susceptible identical twins would both
develop lupus 100% of the time. Environmental factors, therefore,
must also be important. It appears that some people are
genetically predisposed to develop lupus but then must be exposed
to the proper environmental triggers in order to have the disease
(McKhann, 1994).
In conclusion, heredity is involved in the development of lupus
but it is rare to have more than one family member who has lupus.
Much is known about the genetics of lupus, yet even more needs to
be discovered. It is only through careful family studies using
molecular biological techniques that the answer to the genetic
dilemma of SLE and the relationship between heredity and
environment will be solved.
What treatments/possible
cures are available?
Immunosuppressive drugs used in treatment of SLE include
azathioprine (Imuran), alkylating agents (nitrogen mustard,
cyclophosphamide, and chlorambucil). Methotrexate is beneficial
especially in the setting of multi-joint inflammation.
The risk of certain types of infection can be decreased with
immunization (vaccinations). Passive immunization (vaccinating
the patient with a killed virus) poses no problems in lupus
patients. Gammaglobulin is an example of a vaccine, which uses a
nonspecific antibody instead of a live virus. Immunization with
vaccines that use live viruses will result in a lupus flare.
However, polio, measles, and tetanus vaccines, which all use live
viruses, have been given to hundreds of thousands of lupus
patients with no adverse reactions (McKhann, 1994).
Lupus patients may have adverse reactions to allergy shots (immunotherapy).
These people will experience a lupus flare following this
treatment. For this reason, in 1989, the World Health
Organization recommended that patients with autoimmune diseases
should not receive certain types of allergy shots. Allergy shots
could potentially cause the patient to make more anti-DNA and
other lupus-related antibodies in addition to making antibodies
against the agent causing the allergy (Mills, 1994). Some lupus
patients may also experience difficulties after receiving tetanus
or flu vaccines. Antibody levels against the flu virus achieve
only half the desired level for half as long in those with lupus.
About 20% of patients with lupus may feel sick or achy for a few
days following a flu vaccination, where only 10% of non-lupus
patients will suffer such adverse effects following a flu shot (McKhann,
1994).
Drugs such as procainamide or hydralazine can induce the
production of antinuclear antibodies, especially anti-histone
antibodies, and occasionally a SLE-like illness (Hahn, 1987).
Fever, joint pain, arthritis, and serositis can often be managed
effectively by non-steroidal anti-inflammatory drugs (NSAIDs)
alone. NSAIDs are usually well-tolerated, but they are associated
with a range of potential side effects or toxicities, such as
gastrointestinal problems and peptic ulcers (Kotzin, 1986).
Anti-malarial drugs (hydroxycholoroquine, chloroquine, and
quinacrine) are most effective for the management of cutaneous
features of lupus. These drugs are among the safest oral
medications available for treatment (McKhann, 1994).
References:
Alarcón-Segovia, D. et al. 1989. Antiphospholipid antibodies and
the antiphospholipid syndrome in system
lupus erythematosus. A prospective analysis of 500 consecutive
patients. Medicine. Vol. 68, p. 353-365.
Annette Leach Memorial WebPage. Pictures. http://www.hills.net/~rbreske/lupus.htm#PIC
Accessed April 20, 2000.
Asherson, R.A. et al. 1989. Cerebrovascular disease and
antiphospholipid antibodies in systemic lupus
erythematosus, lupus-like disease, and the primary
antiphopholipid antibody syndrome. American Journal of Medicine.
Vol. 86, p. 391-399.
Bluestein, H.G. 1992. The central nervous system in systemic
lupus erythematosus. In Systemic Lupus
Erythematosus. R.G. Lahita, Ed. p. 639-655.
Briley, D.P., B.M. Coull & S.H. Goodnight, Jr. 1989.
Neurological diseases associated with antiphospholipid antibodies.
Annals of Neurology. Vol. 25, p. 221-227.
Hahn, B.H. 1987. Systemic Lupus Erythematosus. Principles of
Internal Medicine. p. 1418-1423.
Harris, E.N., A.E. Gharavi & G.R. Hughes. 1985. Anti-phospholipid
antibodies. Clinical Rheumatic Diseases. Vol. 11, p. 591-609.
Hering, R. et al. 1991. Antiphospholipid antibodies in migraine.
Cephalalgia. Vol. 11, p. 19-21.
The Internet Pathology Laboratory for Medical Education:
Immunpathology Index. http://www-medlib.med.utah.edu/WebPath/IMMHTML/IMMIDX.html
Accessed April, 20 2000.
Janeway CA, Travers P, Walport M, Capra JD. 1999. Immunobiology:
The Immune System in Health and
Disease. 4th ed. New York: Garland Publishing. p 499-500.
Kelley, Keith W., K. Hutchison, R. French, and R. Dantzer.
Central Interleukin-1 Receptors as Mediators
of Sickness. Annals of the New York Academy of Sciences. Vol. 823,
p. 234-246.
Kotzin, B.L. 1986. Systemic lupus erythematosus. Cell Biology.
Vol. 85, p. 303-306.
Krause, I., M. Blank & Y. Shoenfeld. 1996.
Immunointerventions in experimental model for
antiphospholipid syndrome. Annals of Internal Medicine. Vol. 147,
p. 50-53.
Lavalle, C. et al. 1990. Transverse myelitis: A manifestation of
systemic lupus erythematosus strongly
associated with antiphospholipid antibodies. Journal of
Rheumatology. Vol. 17, p. 34-37.
McKhann, G.M. 1994. Clinical trials in a changing era. Annals of
Neurology. Vol. 36, No. 5. p. 683-687.
Mills, J.A. 1994. Systemic lupus erythematosus. New England
Journal of Medicine. Vol. 330, p. 1871-
1879.
National Institute of Arthritis and Musculoskeletal and Skin
Diseases (NIAMS). Health Information: Lupus
Guide. January 26, 1999.
Segal, R., M. Dayan, H. Zinger & E. Mozes. 1995. Methotrexate
treatment in murine experimental systemic lupus erythematosus (SLE):
Clinical benefits associated with cytokine manipulation. Clinical
Experimental Immunology. Vol. 101, p. 66-72.
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