The Disease that cries Wolf
Lupus-In which the bodies immune system
attacks it's own cells-mimics many other illnesses, thwarting
diagnosis. But once identified, new drugs and technologies have
greatly improved the prognosis.
by Monika Guttman
Several years ago, Helen Francisco was tired and achy all the
time, and blamed her fatigue on a series of miscarriages. A hair
stylist who worked out of her home, she gave up the more
lucrative aspects of the job-highlights, permanents, hair
coloring or any other work that involved chemicals-and began
eating a macrobiotic diet to balance her system, hoping with
relief from chemicals and no stress, she would be able to carry
a pregnancy to term. Still, the fatigue would not go away.
Soon she realized a redness on her face was getting more
pronounced. She went to a physician, who recognized the familiar
"butterfly" pattern on her cheeks and nose. Francisco was one of
the lucky ones: she was referred almost immediately to a
rheumatologist, who ran a series of tests and diagnosed her with
systemic lupus erythematosus, or lupus.
Lucky, that is, in that her lupus was diagnosed fairly
quickly. Called the "Great Imitator," lupus is often difficult
to diagnose because it is a systemic disease that can attack the
joints, skin, kidneys, nervous system, lungs, heart and
gastrointestinal tract, mimicking many other illnesses. For many
with the disease, diagnosis can take anywhere from three to ten
years.
Not that Francisco felt particularly lucky. Being diagnosed
with any autoimmune disease like lupus-where the body's immune
system essentially attacks its own cells-can be devastating,
says Rodanthi Kitridou, M.D., professor of medicine, and a
rheumatologist at the LAC+USC Lupus Center, one of the largest
in the country. Kitridou sees between 70 and 80 lupus patients a
month at both LAC+USC and the USC University Hospital. "It is
difficult to explain to patients that their body is attacking
itself and we just don't know why."
What researchers and doctors do know, however, is that new
drugs and technologies have greatly improved the prognosis for
the estimated two million Americans with lupus. Even though
there is no cure for the disease, an extraordinary 80 to 90
percent of all lupus patients can expect to have a normal life
span, thanks to research conducted at places like the USC School
of Medicine. In the 1950s, before steroids were discovered and
used in lupus treatment, the three-year survival rate was closer
to 30 percent, because patients died as their organs
deteriorated from uncontrolled inflammation and damage.
Helping patients with lupus while, at the same time,
furthering research into the disease is the goal of the new
lupus diagnostic and treatment center opening at USC University
Hospital this spring.
Notes David Horwitz, M.D., professor of medicine, molecular
microbiology and immunology, who works on lupus and rheumatoid
arthritis, "With genetic research, we have a better chance of
determining a person's susceptibility to developing lupus. And
by offering clinical trials, we can help improve the prognosis."
The improving prognosis is partly due to the fact that lupus,
which is Latin for "wolf" and so named because the common skin
rashes on the face resemble the markings on a wolf, is getting
more attention, thanks to such celebrities as Charles Kuralt and
former White House dog Millie.
More significantly, progress is due to increased attention
overall to autoimmune diseases, a broad category of conditions
that involve the body's immune system actually mistaking its own
cells for the enemy and turning an "immune response" on itself.
Other autoimmune diseases include multiple sclerosis, ulcerative
colitis, rheumatoid arthritis, psoriasis and diabetes mellitus
(Type I diabetes) and dozens of lesser-known diagnoses with
tongue-twisting names, like ankylosing spondylitis or
antiphospholipid syndrome. While some autoimmune diseases are
mild and only slightly irritating, others can be
life-threatening, extremely painful or debilitating. In all,
autoimmune diseases affect some four million people in the U.S.
alone and cost billions of dollars in health care.
Until fairly recently, however, autoimmune diseases have been
a sort of castaway category in the medical landscape. Diagnosis
is often difficult, because symptoms can go into remission for
no apparent reason or may mimic some other kind of illness.
There are few definitive tests for most autoimmune diseases.
Some have even been on the receiving end of media and medical
skepticism-chronic fatigue syndrome, now considered an
autoimmune disease, was once briefly termed the "yuppie flu"
because it was typically seen in young, middle-class women.
Research also suffered from the fact that autoimmune diseases
affect comparatively limited populations-only two to three
million suffer rheumatoid arthritis, for example, nowhere near
the 23 million who endure migraines or the 16 million with
adult-onset diabetes.
Today the situation is a little different: not only are new
drugs helping manage the symptoms, but thanks to progress in
both genetic research and molecular biology, scientists are
getting a better handle on the immune system in general and,
consequently, on autoimmune diseases. Their goal: to determine
what causes autoimmune diseases in the first place. That, goes
the scientific logic, could lead to a cure.
They face a complicated task, since scientists are still
trying to figure out the complicated choreography of the immune
system itself.
Commissioned as a defending force, the immune system protects
the host body from invasions by foreigners like bacteria,
viruses, fungi or parasites. First, there are the scouts-helper
T-cells that cruise the blood looking for foreign
"antigens"-proteins or carbohydrates that they do not recognize.
If they see a foreign antigen, the scouts send in the troops-B
cells (which have antibody molecules on their surface) and
lymphocytes (hormones). The result is troops attacking the
foreign cells with intent to kill, which usually produces
inflammation. Then the mediators, called suppressor T-cells, get
everybody to calm down by telling the immune system to stop once
the invader has been conquered.
What remains a mystery, however, is how all these cells
communicate. In the case of autoimmune disease, scientists are
investigating if there is a failure to communicate at the scout
level, the troop level or the mediator level-or maybe at all
three levels simultaneously.
As if this system is not complicated enough, the body also
produces lymphocytes that can react against its own cells. At
birth, says Horwitz, "The thymus removes a lot of autoreactive
cells, but basically everyone is left with enough autoreactive
cells to have the potential to develop rheumatoid arthritis,
lupus, multiple sclerosis, myasthenia gravis or any other
autoimmune disease. The immune cells are there with the
potential to turn on these diseases."
Current thinking dictates that the diseases are turned on
through a combination of genetic and environmental factors.
Researchers like Chaim L. Jacob, M.D., Ph.D., associate
professor of medicine and of molecular microbiology and
immunology, are learning that there seems to be a significant
genetic component to lupus, and it may be genes that help
determine whether the autoreactive cells become active. He says
one in 10 lupus patients will have a brother or sister with
lupus. In some other autoimmune diseases, the genetic component
is weaker: in rheumatoid arthritis, maybe one in 100 patients
will have a brother or sister with the condition.
Jacob and others have identified six, possibly seven, genes
that confer susceptibility to lupus. Once all the genes are
noted, there could be a diagnostic test for lupus, he says. At
the present time, Jacob is working with families where one
member has lupus to determine the prevalence and number of the
"lupus genes."
Genetics alone, however, are not a complete trigger for
lupus. For example, one type of lupus, drug-induced lupus,
occurs after the use of certain prescription drugs, like
hydralazine (used to treat high blood pressure or hypertension)
and procainamide (used to treat irregular heart rhythms). What
causes the other two types of lupus (discoid lupus, which
involves only the skin, and systemic lupus) is less well known.
Researchers are focusing on environmental triggers, such as
infections, antibiotics, ultraviolet light, extreme stress, and
certain drugs and chemicals.
Last December, researchers from the University of Oklahoma
announced a study linking the Epstein-Barr virus and lupus. In a
study of 117 patients with systemic lupus, the researchers found
99 percent previously had an Epstein-Barr virus infection.
Although not definitive, the study provides a basis for further
investigation.
Until researchers completely understand the why and how of
autoimmune diseases, however, physicians can only treat the
manifestations of the diseases. They divide immune diseases
generally into two categories: organ-specific and non-organ
specific. In organ-specific autoimmune disorders, the immune
system generally attacks one organ, such as the thyroid gland
(Hashimoto's thyroiditis), adrenal glands (Addison's disease) or
pancreas (insulin-dependent diabetes mellitus). With non-organ
specific diseases, a number of systems are under attack, as in
systemic lupus.
Autoimmune responses can lead to a number of different
results: slow destruction of a specific type of cell or tissue,
overstimulation of an organ or interference with its function.
Most autoimmune diseases trigger inflammation-the reddening and
swelling that normally indicates the body is fighting off an
invader. In systemic lupus, the inflammation symptoms can appear
in a number of places: in the joints, in the membranes that line
different organs like the lungs and heart, on the skin and in
the mouth, or even in the kidneys.
Many systemic lupus patients say there are subtle daily
reminders that all is not perfect for them, even in periods of
remission-they have days of extreme fatigue, for example, or
pains that appear and disappear with no seeming cause. There is
no one pattern to the development of symptoms, either: for one
lupus patient, the first manifestations may be a severe reaction
to sunburn, while for another it could be a muscle weakness.
A prolonged new symptom generally indicates a "flare up"-a
period of active immune reaction triggered by some "event," such
as stress, surgery, drugs or even exposure to sunlight. The
symptoms can appear as something the patient has not experienced
before-Helen Francisco, for example, had one flare up that
involved enormous joint pain in her legs, so she had trouble
standing and walking. With treatment, most of the pain and
weakness went away.
A mild inflammation can be suppressed with aspirin. But more
than likely, says Kitridou, treatment will involve one or a
combination of a number of different drugs designed to stop the
immune reaction and reduce the inflammation, including
corticosteroids (prednisone is the most often prescribed),
anti-malarials (chloroquine or hydroxychloroquine) and
cytotoxic, the newest class of drugs that suppress immune system
activity and dramatically inhibit the destructive effects of
lupus. The three best known are cyclophosphamide, azathioprine
and methotrexate.
For many, the serious side effects of the drugs or simply
having to commit to long periods on medication can be difficult
or demoralizing. Some lupus patients, already having a hard time
reducing the stress and other factors that could trigger
flare-ups, find the weight gain or acne from the steroids make
it difficult to continue with their prescribed regimens.
But the goal of drug therapies, says Kitridou, is to
"minimize damage during an active phase and add to the patient's
quality of life. Lupus is not a 'life sentence,'" since most
people go into extended periods of remission and, thanks to
improved therapies, individuals with lupus are living normal
life spans. "Some cases of lupus are mild, some are severe, but
the majority are somewhere in the middle," observes Kitridou.
The most important aspect in the treatment of lupus, she
says, is that the physician and patient work together. "Lupus
does not automatically go into remission. Patients and
physicians have to engineer the remission." The earlier the
symptom is recognized and treated, the better the outcome, she
adds.
Kitridou is hopeful about new immuno-modulating drugs, like
mycophenolate, that are in clinical trials these days and may be
more effective in stopping the immune reaction that causes the
pain and damage. In addition, biological agents, like
interleukin antigens are being tried against certain substances
involved in the immune response, and there is a trial involving
DHEA that "suggests this steroid may help in improving mild
lupus."
While the investigation into these therapies continues,
however, says Kitridou, "We can control lupus to a great extent.
I'm hopeful there will eventually be a cure."
She adds: "In the meantime, research has made many inroads.
Patients should know lupus can be managed."
