Picture this: a young woman visits her doctor with fatigue, achy joints and anemia. The doctor tells her she’s just losing blood from her period. She should take some iron and she’ll feel better. Or that she’s just tired because she has two kids and a job. If she just gets more sleep, she’ll have more energy.
But nothing she tries makes her symptoms improve. She visits another doctor who tells her she has depression, a viral infection, chronic fatigue or a thyroid problem.
Lupus is an autoimmune disease that disproportionately affects women: 9 out of 10 adults with lupus are women and most women who develop lupus are between the ages of 15 and 44. Yet these scenarios are common for women in the months—or years—before they are diagnosed with the disease, says Grant Hughes, M.D., a rheumatologist at Harborview Medical Center and University of Washington Medical Center.
Some of the most common lupus symptoms—fatigue, joint pain, fever—are also the most nonspecific, says Hughes. It’s not until people get really sick, presenting with something like kidney disease, debilitating arthritis, or a serious skin condition, that most doctors start thinking about lupus.
“Usually people have been sick for months, if not years, before this,” he says.
What is lupus?
Systemic lupus erythematosus (SLE) is the most common form of lupus. Diagnosis is complicated and there is not one national registry to track the disease. But conservative estimates suggest at least 322,000 Americans have SLE, according to the Centers for Disease Control and Prevention. Other forms are cutaneous lupus erythematosus, drug-induced lupus erythematosus and neonatal lupus.
At its base level, lupus is an autoimmune disease, which means the normally protective immune system begins attacking healthy tissues, instead of only protecting against foreign invaders, explains Hughes.
When we think of autoimmune diseases, we often think of the immune system targeting a particular organ or part of the body. But lupus is unique among autoimmune diseases because it’s a systemic disease, says Hughes.
Instead of targeting cells or tissues specific to one organ, lupus targets molecules found in the nucleus of all cells throughout the body. The immune system doesn’t typically have access to this innermost part of a cell, except when cells die and are being cleared out of the body, Hughes explains.
From the blood to skin, liver and gastrointestinal tract, many of the cells in your body are being turned over every day. And that’s when antibodies that attack cell nuclei, called anti-nuclear antibodies (ANA) swoop in.
“Components of dead and dying cells in circulation mix with antibodies and then deposit in the joints, kidneys, skin and other tissues and then trigger inflammation and damage in the organs,” says Hughes.
Many people with lupus feel sick all the time because of this low-grade activation of their immune system, says Hughes.
Around 95 percent of people with lupus test positive for ANA, which is why this blood test is one of the most accurate ways to make a diagnosis. But testing positive for ANA alone does not mean you have SLE. In fact, you can have these antibodies present in your body and be totally healthy, says Hughes.
In order to be diagnosed conclusively with SLE, you have to meet four of 17 clinical and immunological lupus classification criteria. These criteria are helpful for research studies in that they ensure all subjects actually have the disease, says Hughes, but they are so specific that sometimes people get missed. Unless a doctor has a lot of experience in treating lupus, this complexity can make it difficult to make a diagnosis, he says.
“Unfortunately, there are no widely-accepted diagnostic criteria for SLE, and doctors are left using these classification criteria and their best clinical judgement,” says Hughes.
The genetic risk factor
When it comes to why someone will get lupus, the answer is very complex. To some extent, it’s an inherited disease; 70 percent of your risk of developing lupus is in your genes, says Hughes. But that doesn’t mean your parents or grandparents have to have lupus in order for you to get it. In fact, that’s rarely the case, he says.
Sometimes, a parent or sibling will have another autoimmune condition that has the same genetic risk factors as lupus. In other cases, family members will have a positive ANA test, but they aren’t sick at all. And sometimes, there is no trace of lupus or autoimmunity at all in family members.
“Genetics is a big component, but it’s not everything. People inherit susceptibility, but other factors are required to bring the disease out so it’s expressed,” says Hughes. “There’s also randomness, or ‘bad luck’ as some people call it.”
Hormones contribute to women's risk
Researchers know that environmental factors, paired with genes, can contribute to the onset of lupus symptoms. And the fact that most women are diagnosed during their reproductive years also gives researchers a clue as to why this disease is so much more prevalent in young women than in men.
“This really suggests that reproductive factors, particularly hormones, play a role in bringing lupus out in people who are genetically predisposed to getting it,” says Hughes.
Estrogen, specifically, likely contributes to the development of lupus in women who are genetically susceptible, according to a research review, published by Hughes and his colleagues in 2014. Both endogenous estrogen that your body makes and synthetic estrogen in birth control favor the development of lupus, says Hughes.
It is a ‘modulator of risk’ that can increase your odds of developing the disease if you also have other risk factors, says Hughes.
“Estrogen alone is not sufficient to cause lupus, otherwise most women would get lupus,” he says. “You have to have a genetic risk and there are probably some other factors involved. Estrogen is just one of those factors.”
The X chromosome marks the spot
Additional research into why autoimmune disease is more prevalent in women is at the chromosomal level, says Hughes. If you think back to high school biology class, you may remember learning that the genetic difference between male and female are X and Y chromosomes; women have two X chromosomes in every cell of their body, and men have an X chromosome and a Y chromosome.
If both of the X chromosomes in a cell were activated, they would be too powerful for your body to handle. So, during the development of each and every cell in your body, one of the two X chromosomes becomes inactivated. Research suggests that variations in how a woman’s cells do this may affect how the immune system is trained to respond to what the body might consider a threat, causing it to turn against itself.
“This implies males and females are different at the cellular level, not just the organismal level,” he says. “We’re just now unlocking how that contributes to the immune system and autoimmune disease.”
Lupus affects more women of color than white women
On top of the increased risk factor young women already face, black, Hispanic and Asian women are more likely to get lupus than white women—and often experience more severe side effects.
Singer Selena Gomez, who announced in September that she had a kidney transplant due to her lupus, shined a light on the severe complications many minority women experience from the disease.
In a pair of studies in Michigan and Georgia, researchers found that black women developed lupus at a younger age than their white counterparts. They also experienced more life-threatening complications, including lupus-related kidney disease and kidney failure.
A recent study of women in Manhattan found that lupus affects more Hispanic and Asian women than white women in the New York City borough. Like the women observed in previous studies, their lupus was also more likely to be severe and lead to organ complications.
But most people studying the question agree that there are, indeed, clear ethnic and racial differences in lupus prevalence, severity and outcomes, he says. And these differences reflect differences in genetic, socio-economic and environmental variables that are closely linked to ethnicity and race.
More research is needed to further examine why sex, race and ethnicity can change disease likelihood, says Hughes. Talk with your doctor if you have concerns about your health, he says, as early lupus diagnosis and treatment can help prevent some of the more severe complications.