For 41-year-old Judy Pate, it started in June 2006 with nervousness, a pounding heart and shaky legs that were so weak it was so hard to climb the stairs to her Boston apartment. A few weeks later, having missed three days of work with what she thought was the flu, she finally received her diagnosis: Graves' disease, a form of hyperthyroidism, caused by an overproduction of thyroid hormone.

Catherine Thomas's diagnosis came 22 years ago, the day she woke up and found she couldn't walk without help. With three daughters under the age of six to care for, she was terrified. But when she heard the diagnosis, she was more mystified than fearful—lupus, something she'd never heard of.

Cindy Baglietto saw a podiatrist three times in the winter of 2006 before she finally got the right diagnosis for the excruciating pain in her hands and feet, pain so severe it felt as if every finger were broken: rheumatoid arthritis.

And Cindy Holzer, herself a health education and gym teacher, had to nearly lose her vision before she finally figured out what was going on in her body and went to the doctor. Her diagnosis: Type 1 diabetes.

While the four women have very different diseases, their conditions share one thing: They're all autoimmune diseases, caused by an out-of-whack immune system.

More than 80 autoimmune diseases have been identified so far, making the category as a whole the third most common major illness in the United States, affecting about one in 31 Americans.¹ And for reasons we still don't understand, women are far more likely to develop many of these diseases.²

"It's really shocking when you put all the numbers together," says Caroline Whitacre, PhD, professor in the department of molecular virology, immunology and medical genetics at Ohio State University in Columbus. She led a task force of autoimmune experts in 1998 that summarized what was currently known about sex differences in autoimmunity and developed an agenda for future research.

While women overall are 2.3 times more likely than men to develop an autoimmune disease, the sex disparities vary depending on the disease.¹ For instance, women are five times more likely to develop hypothyroidism, up to nine times more likely to develop systemic lupus erythematosus (SLE), three to four times more likely to develop Graves' disease, three times more likely to develop rheumatoid arthritis and scleroderma, and twice as likely to develop multiple sclerosis. Plus, nine out of 10 people with Sjögren's syndrome are women.^1,3,4,5

Most researchers agree on one thing: sex hormones must be involved. For instance, symptoms of multiple sclerosis and rheumatoid arthritis tend to improve during pregnancy, when levels of estrogen and progesterone are high. They also tend to improve when women take oral contraceptives, which moderate hormone fluctuations.² Autoimmune thyroid disease also may improve during pregnancy, then flare after delivery as postpartum thyroiditis.

Lupus, however, might sometimes flare during pregnancy while some other autoimmune diseases show no hormone-related disease changes.²

Another theory suggests that fetal cells from earlier pregnancies that remain in a woman's blood for years after giving birth may play a role in some diseases, particularly those that first develop or get worse after pregnancy.²

We also know that many immune cells have receptors for sex hormones, says Dr. Whitacre. When hormones bind, or attach, to these immune cells, they can affect the cell's behavior. In fact, women tend to have a stronger inflammatory immune response than men, and inflammation is a key component of many autoimmune diseases.²

"So it's that very close relationship with hormones that provides a clue that they play a big role in autoimmune diseases," says Dr. Whitacre.

While hormones may help explain why women are more likely to develop these diseases than men, they aren't behind the actual diseases themselves. For that, blame the immune system.

The immune system developed to protect us from a myriad of foreign invaders. Without its constant vigilance, we wouldn't last a minute. But its very complexity makes it more vulnerable to genetic hiccups that can lead to gene mutations or changes. In some people, those changes increase the risk of developing an autoimmune disease.

It takes more than a few rogue genes to develop an autoimmune disease, however; it may take an environmental trigger.⁶ In some instances, it seems, that trigger might be a virus, even a flu virus. When the immune system mobilizes to fight that virus, some genetic switch flips on or off and instead of slowing down after the virus is eradicated, the immune system keeps going, turning on your own cells. They could be insulin-producing beta cells, as in Type 1 diabetes, bone and joint cells as in rheumatoid arthritis, or thyroid gland cells, as in thyroid diseases. Next thing you know, you've got an autoimmune disease.

Here's a look at three of the most common autoimmune diseases in women: lupus, rheumatoid arthritis and Type 1 diabetes.

Systemic Lupus Erythematosus (SLE)

The rash started in 1984. "I was kind of nervous about it but afraid to do anything about it," recalls Catherine Thomas of Lake Charles, LA. Finally, she worked up the courage to see a dermatologist. He told her she had lupus but not to worry. So she didn't.

Until the day three months later when she couldn't walk unassisted. That's when the doctor biopsied the rash. Eventually this led to a diagnosis of systemic lupus—a far more serious disease than the dermatological version.

Ms. Thomas's difficulties in getting a diagnosis aren't unique. Women often wind up going from doctor to doctor before finally receiving a definitive diagnosis of lupus, says Joan T. Merrill, MD, medical director of the Lupus Foundation of America and head of the Clinical Pharmacology Research Program at Oklahoma Medical Research Foundation in Oklahoma City. That's because there isn't one specific test to diagnose the disease, although some combinations of symptoms and tests can rule it in or out.

Common symptoms include achy and swollen joints, fever, prolonged or extreme fatigue, skin rashes and anemia. Others include sun or light sensitivity, problems with the kidneys, seizures, mouth or nose ulcers and hair loss.⁷ The condition most often strikes women between the ages of 15 and 45,⁸ and is three times more common among African-American women than Caucasian women.⁸

Unlike some other autoimmune conditions, like rheumatoid arthritis, medications to treat lupus have been slow to come to market. One reason is that lupus is a hard disease to study, Dr. Merrill says, because it waxes and wanes on its own, making it difficult to determine if a potential drug has an effect.

But with more investment in lupus research, she expects to see new, more precisely targeted drugs within a few years. These drugs should be more effective and have fewer side effects than drugs currently available.

Ms. Thomas, 54, has been lucky; more than 20 years after her diagnosis, she hasn't suffered any serious organ or heart damage. Her lupus primarily affects her central nervous system, muscles and joints. To reduce flares, she learned to watch her stress level, noting that "one thing I learned early on is that lupus is all about balance and knowing your limits."

Today she takes steroids and anti-malarial drugs to keep her disease in check and says she hasn't had a flare in eight years. But she remembers well the days when she took 19 different medications, spending more than $1,000 a month in medical bills.

She's also learned to remain positive, something many of her friends find hard to believe. "I tell them that even though lupus changes your life, it doesn't have to change it for the worst. And when you learn that, you'll learn that you're in control of your disease."

Rheumatoid Arthritis

Scott Zashin, MD, has never enjoyed his job so much. The Dallas-based rheumatologist, who is a clinical assistant professor at the University of Texas's Southwestern Medical School, finally has an entire arsenal of effective drugs to treat the pain and disability that affects his rheumatoid arthritis patients.

The drugs come in two categories: traditional disease modifying anti-rheumatic drugs (DMARDs) like methotrexate, sulfasalzine (Azulfidine), leflunomide (Arava) and hydroxychloroquine (Plaquenil); and, for those who don't respond to DMARDs, biologic agents like TNF blockers adalimumab (Humira), etanercept (Enbrel) and infliximab (Remicade), or the newer biologic agents abatacept (Orencia) and rituximab (Rituxan), which block specific components of the immune system involved in inflammation. The drugs are very expensive, however, making them difficult to afford for people without insurance or with high co-payments.

"The drugs have changed the outlook for patients with rheumatoid arthritis," says Dr. Zashin. "They're not without potential side effects, but they took people with tremendous amounts of inflammation, who couldn't work or enjoy their lives, and within a month or two that pain just melted away, and these people were living normal lives."

Without treatment, rheumatoid arthritis is a progressive disease that quickly damages bone, joints and tendons, leading to tremendous disability. That's why early treatment is so important, says Dr. Zashin. "We know that within the first two years (after diagnosis) at least half of those with the disease may have damage in their joints on x-rays."

Unlike its sister disease, osteoarthritis, rheumatoid arthritis typically strikes young adults between the ages of 20 and 50 and is particularly prevalent in women of childbearing age. Like most other autoimmune diseases, there is no single laboratory test for its diagnosis, although a laboratory test that identifies antibodies to cyclic citrullinated peptides (CCPs) is showing promise.⁹ Generally, however, diagnosis is based on a variety of indications, including morning stiffness and arthritis in three or more joints, high levels of rheumatoid factor antibodies and changes seen on x-rays.

That's how Cindy Baglietto was first diagnosed. She began exhibiting symptoms in early December, finding it hard to walk in the morning or if she'd been off her feet for a while. "It felt like the bottom of my foot was severely bruised," she said. Soon thereafter, her hands started hurting so badly she couldn't open doors with a key. As a Realtor based in Plano, TX, that made doing her job difficult, as did the crushing fatigue. Finally, after discussing her symptoms with her aunt, who is a nurse, she made an appointment with a rheumatologist and was diagnosed with rheumatoid arthritis.

Type 1 Diabetes

Kathi Hozler refuses to let diabetes hold her back. The 48-year-old woman from Jackson Hole, WY, was diagnosed with what many consider to be a childhood disease when she was 40. Despite having to test her blood sugar more than 10 times a day and take regular injections of insulin, a typical summer day for her consists of a two-hour bike ride, a couple of hours training for a water skiing tournament, a game of tennis with her husband and an early evening run with her daughter.

She manages this level of physical activity by being, in her words, over vigilant about her blood sugar and her disease, taking an active role in both. "Diabetes is a disease where you have to become the doctor," she says.

Many people might be surprised to learn that Type 1 diabetes is an autoimmune disease. Although Type 2 diabetes, in which an individual's cells become resistant to insulin, is more prevalent in this country, Type 1, in which the immune system destroys insulin-producing beta cells, comes on more suddenly and can be more dangerous.

For instance, no amount of diet or exercise ever eliminates the need for insulin in someone with Type 1 diabetes as it can in someone with Type 2, and the typical complications of diabetes —nerve, eye and kidney damage, as well as heart disease—tend to strike earlier and more severely.

Interestingly, the fact that Type 1 is an autoimmune disease may lie behind its eventual cure, says Francine Kaufman, MD, professor of pediatrics at the Keck School of Medicine of the University of Southern California in Los Angeles. "Right now in some patients who are newly diagnosed with Type 1, we know there are some beta cells still alive that, over time, will be destroyed. To save them, we have to unlock the mysteries of the immunological system and try to induce tolerance," so the immune cells won't attack beta cells. Efforts to do that are already under way.

Dr. Kaufman is used to seeing older patients like Ms. Holzer and notes that Type 1 diabetes can occur at any age. Some people, she says, may have had low levels of autoimmunity throughout their life until something like a virus flips that genetic switch and sends the immune system into overdrive. Yet many doctors diagnose these patients with Type 2 diabetes—even though they don't fit the typical profile of the overweight, sedentary person who develops Type 2.

That happened to Ms. Holzer. When she first went to her doctor with symptoms of diabetes, including significant weight loss, enormous thirst and urine output and vision loss, he assumed she had Type 2 diabetes and tried to treat her high blood sugar levels with the oral medication often used for that disease. She knew she needed insulin, however, and drove two hours outside her small town to find a diabetes specialist. Since then, she says, she's been through several doctors before finally finding one who "treats me as a whole person."

Like other women interviewed here, Ms. Holzer emphasizes the importance of a positive outlook when it comes to a chronic disease like diabetes. "You have to make the best of a tough situation," she says. She also notes how important it is that women learn to advocate for themselves with health care professionals and become educated about their diseases. X

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