Authors: Rita Baron-Faust,Jill Buyon
The Autoimmune Connection: Essential Information for Women on Diagnosis, Treatment, and Getting On With Your Life (11 page)
The Shadow of the Wolf—Systemic Lupus Erythematosus
I probably started developing lupus when I was in high school. I remember I had all these weird symptoms my sophomore year. I had red splotches on the bottoms of my hands and the soles of my feet; I thought they were blisters and would actually poke them with a pin. Then I started getting swollen joints, and I was terribly stiff. I remember one time I was at the beach with my friends, and I couldn’t even lift myself off the blanket. My parents got worried and took me to a big hospital, and I was told I had juvenile rheumatoid arthritis. I was put on prednisone for a year. It made my face look all puffy and really wrecked my self-esteem, but the symptoms went away. I basically forgot about it until I went away to college and started feeling ill. I had fevers, I was fatigued, I had difficulty concentrating. At first I thought it was stress.
But then my joints started to feel swollen and painful. And no one seemed to know what was wrong with me. I’m trying to cope with college life, I wanted to keep my grades up, and here I was constantly seeing doctors, getting tests. It still took them a while to finally tell me I had lupus. Eventually, it affected my kidneys, my intestines, and my brain. Now when I think back, I think this disease was sort of shadowing me for years.
D
EANNA
, 33
L
upus means “wolf” in Latin, and as it did with Deanna, it can stalk you silently over a period of years or strike suddenly without warning,
snarling and scratching the skin of the face and vital organs. Systemic lupus erythematosus, or SLE, is a leading cause of kidney disease in younger women, especially those who are African American, and it can lead to premature cardiovascular disease (hardening of the arteries and heart attacks). In recent years, there has been a troubling rise in deaths from lupus, especially among middle-aged black women. However, in most cases lupus is a chronic disease that can be managed with medication. Many women—like Deanna, who’s now married and teaching full-time—live active lives. Importantly, it can be a complicated disease since it affects many different organs, sometimes requiring multiple medications, some of which can put you at risk for other health problems, such as osteoporosis.
Lupus emerges most often between ages 15 and 40, affecting 10 times as many women as men.
1
More African American, Latina, Asian, Native American, and Alaskan native women are affected than Caucasians, with a rate two to three times greater among black women, or about 1 in 500.
1
,
2
Exact prevalence figures vary. According to the National Institutes of Health, between 350,000 and 500,000 people may be affected. Other data estimate the number of lupus patients in the United States at 250,000.
Unlike other autoimmune diseases that target a single organ, like thyroid disease, lupus can affect just about any organ or tissue in the body—including the joints, the kidneys, the heart, the blood, the lungs, and even the nervous system. Some forms of lupus are limited to the skin, like
discoid lupus
(which can occur by itself or as part of the systemic disease). Ten percent of women initially diagnosed with discoid lupus may eventually develop systemic disease.
As with other autoimmune diseases, lupus can be challenging to diagnose because the signs (what the doctor can see) and symptoms (what you may experience) can occur separately over time. So it may be months or even years before enough symptoms are present to clearly meet the classification criteria for lupus (see
pages 70
to
71
). A survey conducted by the Lupus Foundation of America found that half of lupus patients had symptoms for five years before obtaining a diagnosis, consulting three or more doctors before being correctly diagnosed.
Lupus often mimics other diseases. It may be initially diagnosed as rheumatoid arthritis because the first problems seen can be joint pain and stiffness of the hands, wrists, and knees. Fatigue and depression may be mistaken for
chronic fatigue syndrome or major depression. Pain and color changes of the fingers in cold weather, called
Raynaud’s phenomenon
, can occur in lupus but are common in scleroderma. Dry eyes and mouth suggest Sjögren’s syndrome. In fact, as many as a third of women with lupus may have other autoimmune diseases. Symptoms of a second disease may often be attributed to lupus, resulting in a delay in diagnosis. Arthritis is the most common symptom, seen in around 84 percent of women with lupus.
The precise cause of lupus is not known. In SLE, antibodies attack healthy cells—even specific parts of those cells. These include antibodies to components of the cell nucleus, the yolk-like structure in the center of each cell that contains your DNA. Various forms of
antinuclear antibodies (ANAs)
can be associated with skin rashes or damage the kidneys. Other antibodies attack
proteins on the cell surface resulting in low white blood cell, platelet, or red blood cell counts. Some autoantibodies result in an increased risk of clotting.
The B cells that produce autoantibodies and directly (as in the case of platelets) or indirectly (as in the case of the kidney) cause inflammation and damage in autoimmune diseases need to be activated by helper T cells. In lupus these B and T cells may be hyperactive, and the regulatory mechanisms that keep this imbalance in check may not be working properly.
A “suicide program,”
apoptosis
, is built into every cell and is necessary to eliminate defective cells, cancer cells, cells produced because of too-rapid growth in certain tissues, and lymphocytes that are no longer needed once a particular immune response has ended. This suicide program can be activated by genes within a cell, damage to DNA (such as sun damage from ultraviolet light that can lead to skin cancer), signals sent to cells by cytokines, or even by an infection.
During apoptosis, the contents of the dying cells are spilled out into the bloodstream to be gobbled up by neutrophils or macrophages and eliminated by the body. In lupus, these clearance systems may not be working properly. So the debris from these dying cells—which contain fragments of the cell nuclei—may cause the body to produce those antinuclear autoantibodies, which then attack healthy tissues, explains Bevra H. Hahn, MD, professor of medicine at the University of California, Los Angeles, a noted lupus researcher.
At the same time, the problems of cell suicide programming that promote autoreactivity may also be exaggerated as T cells that inappropriately react with self are not properly regulated. In lupus there may be a genetic predisposition. A person could be born with a defect in a gene that controls apoptosis or other regulatory aspects relating to keeping the immune system in check. In some women genetically destined to get lupus, self-reactive cells may escape destruction during fetal development and produce autoantibodies later in life. An anti-suicide molecule called
B cell activating factor (BAFF)
, also called B-lymphocyte stimulator (BLyS), interferes with apoptosis and enhances the proliferation and survival of autoimmune B cells. The first new treatment approved for lupus in 50 years,
belimumab (Benlysta)
, blocks the effects of BLyS and reduces abnormal B cells (see
pages 77
to
78
).
Immune complexes also play a major role in lupus. These latticelike structures are formed when antibodies bind to their targets and build up in tiny
blood vessels. Accumulation of immune complexes causes blood vessel inflammation and even blockage, and blood clots (caused by
lupus anticoagulant antibodies
) can also block off vessels supplying vital organs.
Proteins called
complement
normally dissolve immune complexes or prevent them from growing too large. Women with lupus may have genetic defects in the complement system, producing too little complement to keep up with rapidly forming immune complexes, or it gets used up too quickly. “Lupus seems to be a problem of regulation that allows increased rates of cell death in circulating lymphocytes, decreased clearance of cellular debris, sustained production of autoantibodies, and the increased formation of immune complexes, which cause organ damage,” concludes Dr. Hahn. Simply put: lupus both clogs and corrodes aspects of the body’s plumbing system—be it in blood vessels or other tissues. When complement is activated by autoantibodies, the resulting protein fragments of complement can also cause inflammation in organs.
The genes that control these processes may be among many that contribute to lupus. So far, around 35 genes have been linked to lupus, many of them involving complement.
3
The strongest genetic risk factor for lupus is a gene called
C1q
, which encodes a complement protein. Among other things, this protein coats apoptotic cells and helps them to be cleared before antigens on their surface are recognized and targeted by the immune system. When C1q is completely absent (which is rare), the risk of lupus can be as high as 90 percent.
4
Genetic mutations have also been found in complement receptors 2 and 3, the latter associated with lupus nephritis. Another problem may lie with the receptor for the
Fcγ
(gamma) gene, which clears immune complexes.
The genetic defects that contribute to lupus appear to run in families. The chance of two sisters having lupus is 2 to 10 percent, but if they are identical twins (who share the same genes), the chances of both having lupus increases to 25 percent or more. Several centers around the country are collecting and studying genetic data from thousands of lupus patients and family members, and new discoveries are being made all the time.
But genes alone are not enough. An environmental trigger like a drug or a virus could also play a role in triggering lupus in genetically vulnerable women. A virus that inhibits normal cell death could allow infected cells to multiply. Since 1971, studies have implicated
Epstein-Barr virus (EBV)
, which
infects B cells and is periodically reactivated.
5
This reactivation could be a source of chronic immune system stimulation and, in theory, could cause increased production of lupus autoantibodies (and possibly disease flares), says Dr. Hahn.
One study by researchers at the Oklahoma Medical Research Foundation and Case Western Reserve University in Cleveland, Ohio, looked at 196 lupus patients and compared them to 392 healthy people matched for age and sex; all but one of the lupus patients had been exposed to EBV at some point, compared to 94 percent of the control group.
In rare cases, lupus can be triggered by drugs, including antibiotics like minocycline, often used to treat chronic acne; procainamide, prescribed for irregular heartbeats; hydralazine, used to treat hypertension; and isoniazid, used to treat tuberculosis. In these cases, the disease usually disappears when the drug is stopped. Environmental toxins may also be triggers.
Then there are hormones. Some studies have suggested that women with SLE have abnormalities processing estrogen and testosterone. Although estrogen is the main female sex hormone, women also produce male hormones,
androgens
, including testosterone. Androgens play a variety of roles in the body, affecting bone density, muscle strength, energy, well-being, sex drive (libido), and possibly immune system function. Women with lupus are also thought to have low levels of testosterone. (For more, see
page 80
).
Deanna’s story continues:
I chiefly remember how difficult it was for me my first two years of college.
I was under enormous pressure. Keeping my grades up was very important to me, but it was a struggle just to get out of bed some days. I had a lot of joint pain; I had headaches. At this point I was running back and forth to hospitals, getting all kinds of tests done. It was so hard for me to concentrate on anything. I usually grasp things pretty quickly, but even the simplest things would take me hours to absorb. I know now that I was experiencing a lupus flare. But my doctors still hadn’t figured out what was wrong. I also developed skin lesions on my buttocks—raised red marks, like scabs. I had every test you could think of. It was very stressful. First they said I had vasculitis and that I needed to take steroids. So I found myself back on prednisone and I had the side effects again, the moon face, the hair loss, the weight loss . . . at one point, I was down to ninety pounds. I took steroids my entire
sophomore year, but they didn’t help. I was getting progressively worse. And I started experiencing blurry vision in my right eye. It was very frightening. I just figured I was stressed out with all the tests and the medication. Then they did more tests and said I had optic neuritis, my blood pressure was up, and they found blood and protein in my urine. The lupus had moved into my kidneys. Only then was I finally diagnosed with lupus.
Any one of the warning signs we’ve listed may herald lupus, but the disease can show itself differently in each woman. It often begins with vague joint pains and fever. You may almost feel like you have the flu—achy and feverish, with swollen glands and fatigue. For some women, like Deanna, there are memory and concentration problems, dubbed a lupus “fog.”
Approximately half of women with lupus will have skin rashes, including a classic
malar
or “butterfly” rash. This is a raised, red rash that spreads across the bridge of the nose (the body of the butterfly) and across the cheeks (the wings). Lupus actually got its name from the rash; some people thought it made the face look like it was mauled by a wolf (
erythema
means “red skin”). This rash is quite different from acne, but may be confused with rosacea. In acne, you can see redness and pimples anywhere on the face; the lupus rash does not extend into the folds alongside the nose and mouth. Discoid lupus usually has plugged follicles, patchy hair loss, and scaly lesions. In
subacute cutaneous lupus erythematosus
, you develop a very sun-sensitive, red rash.
In fact, a rash or other skin problem is often the first clue that a woman may have lupus. Sensitivity to the ultraviolet rays of the sun (
photosensitivity
) can also produce or worsen skin rashes (sunscreen is a must when you have lupus).
Fatigue is a common symptom of many autoimmune diseases; around 90 percent of women with SLE may experience fatigue.
6
In lupus, fatigue may be due to
anemia
(a lowered red blood cell count), difficulty breathing, or muscle weakness. You may also have lower white blood cell counts (
leukopenia
and/or
lymphopenia
), which make you more susceptible to infections, or a low platelet count (
thrombocytopenia
) that causes unexplained black-and-blue marks and increases the risk of bleeding after something as routine as
brushing your teeth. More than three-quarters of women with lupus may also have depression.
3
This may be partly due to fatigue or feeling unwell. Migraine headaches may also be a problem.
You may have arthritis, with tender, swollen, and painful joints. Hair loss (
alopecia
) may accompany a lupus flare. If your kidneys are affected, you may see some fluid retention, most commonly as swollen ankles and at times swelling up to the knees. The kidneys are responsible for filtering waste products from the body and excreting them; when the kidneys aren’t functioning well, it affects the balance of fluid and salt in the body. When the kidneys’ filtering system is damaged, it can cause too much protein to leak into the urine (
proteinuria
). Blood pressure may also be elevated.
Ethnicity and race may affect how severe your lupus is. According the Lupus Foundation of America, Latinas, African Americans, and Asians are three times more likely to develop lupus, and studies suggest they are more likely than Caucasians to have disease worsening and organ impairment.
7